DE60223923T3 - PROGRUGS OF GABA ANALOGUE, COMPOSITIONS AND ITS USES - Google Patents

Abstract

The present invention provides prodrugs of GABA analogs, pharmaceutical compositions of prodrugs of GABA analogs and methods for making prodrugs of GABA analogs. The present invention also provides methods for using prodrugs of GABA analogs and methods for using pharmaceutical compositions of prodrugs of GABA analogs for treating or preventing common diseases and/or disorders

Description

1. Field of the invention

The present invention relates generally to prodrugs of GABA analogs, to pharmaceutical compositions of prodrugs of GABA analogs, to methods for preparing prodrugs of GABA analogs, to prodrugs of GABA analogs, and to pharmaceutical compositions of prodrugs of GABA analogs for use in methods of treatment and prevention. More particularly, the present invention relates to prodrugs of gabapentin, pharmaceutical compositions of prodrugs of gabapentin, methods for producing prodrugs of gabapentin, prodrugs of gabapentin and pharmaceutical compositions of prodrugs of gabapentin for use in methods of treatment and prevention.

2. Background of the invention

Gamma ("γ") aminobutyric acid ("GABA") is one of the major inhibitory transmitters in the mammalian central nervous system. GABA is not efficiently transported from the bloodstream into the brain (i.e., GABA does not effectively cross the blood-brain barrier). Thus, brain cells provide almost all brain-derived GABA (GABA is biosynthesized by decarboxylation of glutamic acid with pyridoxal phosphate).

GABA regulates neuronal excitability by binding to specific membrane proteins (i.e., GABAA receptors), resulting in the opening of an ion channel. The entry of a chloride ion through the ion channel leads to hyperpolarization of the recipient cell, thus preventing the transmission of nerve impulses to other cells. Low levels of GABA have been reported in individuals with epileptic seizures, movement disorders (eg, multiple sclerosis, intention tremor, tardive dyskinesia), panic, anxiety, depression, alcoholism, and manic behavior.

The implication of low GABA levels in a number of common disease states and / or common medical conditions has elicited an intense interest in producing GABA analogs that have better pharmaceutical properties (eg, the ability to cross the blood brain Barrier). Thus, a number of GABA analogs of considerable pharmaceutical effectiveness have been synthesized in the art (See, e.g., Satzinger et al. U.S. Patent No. 4,024,175 ; Silverman et al. U.S. Patent No. 5,563,175 ; Horwell et al. U.S. Patent No. 6,020,370 ; Silverman et al. U.S. Patent No. 6,028,214 ; Horwell et al. U.S. Patent No. 6,103,932 ; Silverman et al. U.S. Patent No. 6,117,906 ; Silverman, International Disclosure No. WO 92/09560 ; Silverman et al., International Disclosure No. WO 93/23383 ; Horwell et al., International Disclosure No. WO 97/29101 , Horwell et al., International Disclosure No. WO 97/33858 ; Horwell et al., International Disclosure No. WO 97/33859 ; Bryans et al., International Disclosure No. WO 98/17627 ; Guglietta et al., International Disclosure No. WO 99/08671 ; Bryans et al., International Disclosure No. WO 99/21824 ; Bryans et al., International Disclosure No. WO 99/31057 ; Belliotti et al., International Disclosure No. WO 99/31074 ; Bryans et al., International Disclosure No. WO 99/31075 ; Bryans et al., International Disclosure No. WO 99/61424 ; Bryans et al., International Disclosure No. WO 00/15611 ; Bryans, International Disclosure No. WO 00/31020 ; Bryans et al., International Disclosure No. WO 00/50027 ; and Bryans et al., International Disclosure No. WO 02/00209 ).

Pharmaceutically important GABA analogs include, for example, gabapentin (1), pregabalin (2), vigabatrin (3) and baclofen (4), shown above. Gabapentin is a lipophilic GABA analogue that can pass through the blood-brain barrier that has been used since 1994 to clinically treat epilepsy. Gabapentin may also have beneficial therapeutic effects in chronic pain conditions (eg, neuropathic pain, muscular and skeletal pain), psychiatric conditions (eg, panic, anxiety, depression, alcoholism and manic behavior), movement disorders (eg, multiple Sclerosis, intention tremor, tardive dyskinesia), etc. (Magnus, Epilepsia, 1999, 40: S66-S72). Currently, gabapentin is also used in the clinical management of neuropathic pain. Pregabalin, which has greater efficacy than gabapentin in preclinical models of pain and epilepsy, is currently in Phase III clinical trials.

A significant problem with many GABA analogs is the intramolecular reaction of the γ-amino group with the carboxyl functionality to form the γ-lactam, as exemplified below for gabapentin. The formation of γ-lactam (5), because of its toxicity, presents serious difficulties in formulating gabapentin. For example, gabapentin has a toxicity (LD ₅₀ , mouse) of more than 8000 mg / kg while the corresponding lactam (5) has a toxicity (LD ₅₀ , mouse) of 300 mg / kg. Consequently, the formation of by-products such as lactams during the synthesis of GABA analogs and / or formulation and / or storage of GABA analogs or compositions of GABA analogs must be minimized for safety reasons (especially in the case of gabapentin).

The problem of lactam contamination of GABA analogs, particularly in the case of gabapentin, has been partially overcome by the use of special additional purification steps, certain choice of adjunct materials in pharmaceutical compositions, and careful control procedures (Augurt et al. U.S. Patent No. 6,054,482 ). However, attempts to prevent lactam contamination either in the synthesis or storage of GABA analogs, such as gabapentin, or compositions thereof, have not been entirely successful.

Rapid systemic secretion is another significant problem with many GABA analogs, including gabapentin, which consequently require frequent dosing to maintain a therapeutic or prophylactic concentration in the systemic circulation (Bryans et al., Med. Res. Rev., 1999, 19, 19; 149-177). For example, dosage ranges of 300-600 mg gabapentin doses administered three times a day are typically used for anticonvulsive therapy. Higher doses (1800-3600 mg / day in divided doses) are typically used to treat neuropathic pain.

Continued release formulations are a conventional solution to the problem of rapid systemic secretion, as is well known to those skilled in the art (See, eg, "Remington's Pharmaceutical Sciences, Philadelphia College of Pharmacy and Science, 17th Edition, 1985). Osmotic delivery systems are also recognized methods of sustained drug delivery (See, e.g., Verma et al., Drug Dev. Ind. Pharm., 2000, 26: 695-708). Many GABA analogs, including gabapentin and pregabalin, are not absorbed via the colon. Rather, these compounds are typically absorbed in the small intestine by the large neutral amino acid transporter ("LNAA") (Jezyk et al., Pharm. Res., 1999, 16, 519-526). The rapid passage of conventional dosage forms through the proximal absorbent region of the gastrointestinal tract has prevented the successful application of sustained release technologies to many GABA analogs.

Thus, there is a substantial need for effective versions of sustained release GABA analogs to minimize the increased dosage rate due to the rapid systemic secretion of these compounds. There is also a need for pure GABA analogs (especially gabapentin and pregabalin analogs) which are substantially pure and do not spontaneously lactamize during formulation or during storage.

EP 1 178 034 A1 (Warner-Lambert Company) describes prodrugs of pregabalin and other related GABA analogs that are reported to show better absorption from the gastrointestinal tract than pregabalin.

WO 01/90052 A1 (Warner-Lambert Company) describes prodrugs of gabapentin and other related GABA analogs that are reported to show better absorption from the gastrointestinal tract than gabapentin.

3. Summary of the invention

The present invention addresses these and other needs by providing prodrugs of GABA analogs, pharmaceutical compositions of prodrugs of GABA analogs, and methods of producing prodrugs of GABA analogs. The present invention also provides prodrugs of GABA analogs and pharmaceutical compositions of prodrugs of GABA analogs for treating or preventing common diseases and / or conditions.

Significantly, the prodrugs provided by the present invention can have significant pharmaceutical benefits of particular utility in the art. First, the prodrug of the prodrugs of GABA analogs provided by the present invention is typically labile in vivo (ie, it is cleaved either enzymatically or chemically, generating substantial quantities of a GABA analog before the prodrug is derived from a GABA analogue) Patient is excreted). Second, the pro-unit derivative provided by cleavage of prodrug from the prodrug and any metabolite thereof is typically nontoxic when administered to a mammal according to dosage ranges typically met with the GABA analog.

The present invention provides compounds selected from 1 - {[(α-isobutanoyloxyethoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid and pharmaceutically acceptable salts, hydrates and solvates thereof.

In one embodiment, the compound is selected from 1 - {[(α-isobutanoyloxyethoxy) carbonyl]] - aminomethyl} -1-cyclohexaneacetic acid and the sodium salt thereof.

In one embodiment, the compound is 1 - {[(α-isobutanoyloxyethoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid.

In one embodiment, the compound is the sodium salt of 1 - {[(α-isobutanoyloxyethoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid.

The present invention also provides pharmaceutical compositions comprising a compound as described above and a pharmaceutically acceptable vehicle.

In one embodiment, the pharmaceutical composition is a pharmaceutical composition for treating or preventing epilepsy, depression, anxiety, psychosis, fainting, hypokinesia, cranial distress, neurodegenerative disorders, panic, pain, inflammatory diseases, insomnia, gastrointestinal disorders, or alcohol withdrawal syndrome in a patient ,

In one embodiment, the pharmaceutical composition is a pharmaceutical composition for treating or preventing neuropathic pain, muscle pain or skeletal pain in a patient.

The present invention also provides compounds as described above for use in a method of treatment of a human or animal body by therapy.

The present invention also provides compounds as described above for use in a method for treating or preventing epilepsy, depression, anxiety, psychosis, fainting, hypokinesia, cranial, neurodegenerative, panic, pain, inflammatory, insomnia, gastrointestinal, or Alcohol withdrawal syndrome ready in a patient.

The present invention also provides compounds as described above for use in a method of treating or preventing neuropathic pain, muscle pain or skeletal pain in a patient.

The present invention also provides the use of compounds as described above in the manufacture of a medicament for the treatment or prevention of epilepsy, depression, anxiety, psychosis, fainting, hypokinesia, cranial, neurodegenerative, panic, pain, inflammatory, insomnia, gastrointestinal Diseases or alcohol withdrawal syndrome in a patient.

The present invention also provides the use of compounds as described above in the manufacture of a medicament for the treatment or prevention of neuropathic pain, muscle pain or skeletal pain in a patient.

The compounds described herein have a pro-unit attached to the γ-amino group of GABA analogs. This pro-unit may be directly attached to the γ-amino group of a GABA analog or may optionally be attached to the amino group of an α-amino acid pro-unit or to the hydroxy group of an α-hydroxy acid pro unit which itself is attached to the γ-amino group of the GABA analog is, be bound.

The compounds described herein also have a pro-unit attached to the carboxyl group of GABA analogs. The carboxyl pro-unit will typically be an ester or thioester group. A wide variety of ester or thioester groups can be used to form carboxyl pro-units.

Thus, the compounds described herein may include not less than four pro-units, which include one carboxyl pro-unit and up to three amino-pro units attached in sequence to the γ-amino group (ie, such that each sample unit is sequentially terminated from the N-terminal end the GABA analogue is cleaved off). The compounds described herein may contain two amino-pro units and one carboxyl-pro unit, two amino-pro-units, one amino-pro unit and one carboxyl-pro unit or one amino-pro unit. Preferably, for those compounds which contain both an amino-pro-moiety and a carboxyl-pro-moiety, the carboxyl-proe moiety is hydrolyzed prior to complete cleavage of the prodrug (s) bound to the amine moiety.

oder ein pharmazeutisch verträgliches Salz, Hydrat oder Solvat davon beschrieben, wobei:
m, n, t und u unabhängig voneinander 0 oder 1 sind;
X O oder NR¹⁶ ist;
W O oder NR¹⁷ ist;
Y O oder S ist;
R¹ aus Wasserstoff, R²⁴C(O)-, R²⁵OC(O)-, R²⁴C(S)-, R²⁵OC(S)-, R²⁵SC(O)-, R²⁵SC(S)-, (R⁹O)(R¹⁰O)P(O)-, R²⁵S-,

und

ausgewählt ist;
R² jeweils unabhängig voneinander aus Wasserstoff, Alkyl, substituiertem Alkyl, Alkoxy, substituiertem Alkoxy, Acyl, substituiertem Acyl, Acylamino, substituiertem Acylamino, Alkylamino, substituiertem Alkylamino, Alkylsulfinyl, substituiertem Alkylsulfinyl, Alkylsulfonyl, substituiertem Alkylsulfonyl, Alkylthio, substituiertem Alkylthio, Alkoxycarbonyl, substituiertem Alkoxycarbonyl, Aryl, substituiertem Aryl, Arylalkyl, substituiertem Arylalkyl, Aryloxy, substituiertem Aryloxy, Carbamoyl, Cycloalkyl, substituiertem Cycloalkyl, Cycloheteroalkyl, substituiertem Cycloheteroalkyl, Dialkylamino, substituiertem Dialkylamino, Halogen, Heteroalkyl, substituiertem Heteroalkyl, Heteroaryl, substituiertem Heteroaryl, Heteroarylalkyl, substituiertem Heteroarylalkyl, Heteroalkyloxy, substituiertem Heteroalkyloxy, Heteroaryloxy und substituiertem Heteroaryloxy ausgewählt ist oder gegebenenfalls R² und R¹⁶ zusammen mit den Atomen, an die sie gebunden sind, einen Cycloheteroalkyl- oder substituierten Cycloheteroalkylring bilden;
R³ und R⁶ unabhängig voneinander aus Wasserstoff, Alkyl, substituiertem Alkyl, Aryl, substituiertem Aryl, Arylalkyl, substituiertem Arylalkyl, Cycloalkyl, substituiertem Cycloalkyl, Cycloheteroalkyl, substituiertem Cycloheteroalkyl, Heteroaryl, substituiertem Heteroaryl, Heteroarylalkyl und substituiertem Heteroarylalkyl ausgewählt sind;
R⁴ und R⁵ unabhängig voneinander aus Wasserstoff, Alkyl, substituiertem Alkyl, Acyl, substituiertem Acyl, Arylalkyl, substituiertem Arylalkyl, Cycloalkyl, substituiertem Cycloalkyl, Cycloheteroalkyl, substituiertem Cycloheteroalkyl, Heteroarylalkyl und substituiertem Heteroarylalkyl ausgewählt sind oder gegebenenfalls R⁴ und R⁵ zusammen mit dem Kohlenstoffatom, an das sie gebunden sind, einen Cycloalkyl-, substituierten Cycloalkyl-, Cycloheteroalkyl-, substituierten Cycloheteroalkyl- oder verbrückten Cycloalkylring bilden;
R⁸ und R¹² unabhängig voneinander aus Wasserstoff, Acyl, substituiertem Acyl, Alkoxycarbonyl, substituiertem Alkoxycarbonyl, Alkyl, substituiertem Alkyl, Aryl, substituiertem Aryl, Arylalkyl, substituiertem Arylalkyl, Cycloalkyl, substituiertem Cycloalkyl, Cycloheteroalkyl, substituiertem Cycloheteroalkyl, Heteroalkyl, substituiertem Heteroalkyl, Heteroaryl, substituiertem Heteroaryl, Heteroarylalkyl und substituiertem Heteroarylalkyl ausgewählt sind oder gegebenenfalls R⁸ und R¹² zusammen mit den Kohlenstoffatomen, an die sie gebunden sind, einen Cycloalkyl-, substituierten Cycloalkyl-, Cycloheteroalkyl- oder substituierten Cycloheteroalkylring bilden;
R¹¹ aus Wasserstoff, Alkyl, substituiertem Alkyl, Acyl, substituiertem Acyl, Aryl, substituiertem Aryl, Arylalkyl, substituiertem Arylalkyl, Carbamoyl, Cyano, Cycloalkyl, substituiertem Cycloalkyl, Heterocycloalkyl, substituiertem Heterocycloalkyl, Heteroaryl, substituiertem Heteroaryl, Heteroarylalkyl, substituiertem Heteroarylalkyl, Alkoxycarbonyl, substituiertem Alkoxycarbonyl, Cycloheteroalkyloxycarbonyl, substituiertem Cycloheteroalkyloxycarbonyl, Aryloxycarbonyl, substituiertem Aryloxycarbonyl, Heteroaryloxycarbonyl, substituiertem Heteroaryloxycarbonyl und Nitro ausgewählt ist;
R⁷, R⁹, R¹⁰, R¹⁵, R¹⁶ und R¹⁷ unabhängig voneinander aus Wasserstoff, Alkyl, substituiertem Alkyl, Aryl, substituiertem Aryl, Arylalkyl, substituiertem Arylalkyl, Cycloalkyl, substituiertem Cycloalkyl, Cycloheteroalkyl, substituiertem Cycloheteroalkyl, Heteroalkyl, substituiertem Heteroalkyl, Heteroaryl, substituiertem Heteroaryl, Heteroarylalkyl und substituiertem Heteroarylalkyl ausgewählt sind;
R¹³ und R¹⁴ unabhängig voneinander aus Wasserstoff, Alkyl, substituiertem Alkyl, Alkoxycarbonyl, substituiertem Alkoxycarbonyl, Aryl, substituiertem Aryl, Arylalkyl, substituiertem Arylalkyl, Carbamoyl, Cycloalkyl, substituiertem Cycloalkyl, Cycloalkoxycarbonyl, substituiertem Cycloalkoxycarbonyl, Heteroaryl, substituiertem Heteroaryl, Heteroarylalkyl und substituiertem Heteroarylalkyl ausgewählt sind oder gegebenenfalls R¹³ und R¹⁴ zusammen mit dem Kohlenstoffatom, an das sie gebunden sind, einen Cycloalkyl-, substituierten Cycloalkyl-, Cycloheteroalkyl- oder substituierten Cycloheteroalkylring bilden;
R²⁰ und R²¹ unabhängig voneinander aus Wasserstoff, Acyl, substituiertem Acyl, Alkyl, substituiertem Alkyl, Aryl, substituiertem Aryl, Arylalkyl, substituiertem Arylalkyl, Cycloalkyl, substituiertem Cycloalkyl, Cycloheteroalkyl, substituiertem Cycloheteroalkyl, Heteroalkyl, substituiertem Heteroalkyl, Heteroaryl, substituiertem Heteroaryl, Heteroarylalkyl und substituiertem Heteroarylalkyl ausgewählt sind oder gegebenenfalls R²⁰ und R²¹ zusammen mit dem Kohlenstoffatom, an das sie gebunden sind, einen Cycloalkyl-, substituierten Cycloalkyl-, Cycloheteroalkyl- oder substituierten Cycloheteroalkylring bilden;
R²² und R²³ unabhängig voneinander aus Wasserstoff, Alkyl, substituiertem Alkyl, Aryl, substituiertem Aryl, Arylalkyl und substituiertem Arylalkyl ausgewählt sind oder gegebenenfalls R²² und R²³ zusammen mit dem Kohlenstoffatom, an das sie gebunden sind, einen Cycloalkyl-, substituierten Cycloalkyl-, Cycloheteroalkyl- oder substituierten Cycloheteroalkylring bilden;
R²⁴ aus Wasserstoff, Acyl, substituiertem Acyl, Alkyl, substituiertem Alkyl, Aryl, substituiertem Aryl, Arylalkyl, substituiertem Arylalkyl, Cycloalkyl, substituiertem Cycloalkyl, Cycloheteroalkyl, substituiertem Cycloheteroalkyl, Heteroalkyl, substituiertem Heteroalkyl, Heteroaryl, substituiertem Heteroaryl, Heteroarylalkyl und substituiertem Heteroarylalkyl ausgewählt ist und
R²⁵ aus Acyl, substituiertem Acyl, Alkyl, substituiertem Alkyl, Aryl, substituiertem Aryl, Arylalkyl, substituiertem Arylalkyl, Cycloalkyl, substituiertem Cycloalkyl, Cycloheteroalkyl, substituiertem Cycloheteroalkyl, Heteroalkyl, substituiertem Heteroalkyl, Heteroaryl, substituiertem Heteroaryl, Heteroarylalkyl und substituiertem Heteroarylalkyl ausgewählt ist.Here are compounds of formula (I), formula (II) or formula (III):

or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
m, n, t and u are independently 0 or 1;
X is O or NR ¹⁶ ;
WO or NR ¹⁷ ;
YO or S is;
R ^{1 is} hydrogen, R ²⁴ C (O) -, R ²⁵ OC (O) -, R ²⁴ C (S) -, R ²⁵ OC (S) -, R ²⁵ SC (O) -, R ²⁵ SC (S ) -, (R ⁹ O) (R ¹⁰ O) P (O) -, R ²⁵ S-,

and

is selected;
R ^{2 are} each independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino, alkylsulfinyl, substituted alkylsulfinyl, alkylsulfonyl, substituted alkylsulfonyl, alkylthio, substituted alkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryloxy, substituted aryloxy, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino, halogen, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkyloxy, substituted heteroalkyloxy, heteroaryloxy and substituted heteroaryloxy, or optionally R ² and R ¹⁶ together with the atoms to which they are bonded to form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
R ³ and R ^{6 are} independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl;
R ⁴ and R ^{5 are} independently selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroarylalkyl and substituted heteroarylalkyl, or optionally R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl or bridged cycloalkyl ring;
R ⁸ and R ¹² are each independently selected from hydrogen, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, Heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl, or optionally R ⁸ and R ¹² together with the carbon atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;
R ^{11 is} hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cyano, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, alkoxycarbonyl , substituted alkoxycarbonyl, cycloheteroalkyloxycarbonyl, substituted cycloheteroalkyloxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, heteroaryloxycarbonyl, substituted heteroaryloxycarbonyl and nitro;
R ⁷ , R ⁹ , R ¹⁰ , R ¹⁵ , R ¹⁶ and R ^{17 are} independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted Heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl;
R ¹³ and R ^{14 are} independently selected from hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted Heteroarylalkyl or optionally R ¹³ and R ¹⁴ together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;
R ²⁰ and R ²¹ are each independently selected from hydrogen, acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, Heteroarylalkyl and substituted heteroarylalkyl, or optionally R ²⁰ and R ²¹ together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;
R ²² and R ^{23 are} independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl and substituted arylalkyl, or optionally R ²² and R ²³ together with the carbon atom to which they are attached, a cycloalkyl, substituted cycloalkyl , Cycloheteroalkyl or substituted cycloheteroalkyl ring;
R ^{24 is selected} from hydrogen, acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl is and
R ^{25 is selected} from acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl.

In a second aspect, the present invention provides pharmaceutical compositions of compounds of the invention. The pharmaceutical compositions generally comprise one or more compounds of the invention and a pharmaceutically acceptable vehicle.

In a third aspect, the present invention provides compounds for use in methods of treating or preventing epilepsy, depression, anxiety, psychosis, fainting, hypokinesia, craniomyopathy, neurodegenerative disorders, panic, pain (especially neuropathic pain and muscular and skeletal pain), inflammatory diseases (ie arthritis), insomnia, gastrointestinal disorders or alcohol withdrawal syndrome. The methods generally include administering a therapeutically effective amount of a compound of the invention to a patient in need of such treatment or prevention.

In a fourth aspect, the present invention provides pharmaceutical compositions for treating or preventing epilepsy, depression, anxiety, psychosis, cerebral fits, hypokinesia, cranial disorders, neurodegenerative disorders, panic, pain (especially neuropathic pain and muscular and skeletal pain), inflammatory diseases (ie, arthritis ), Insomnia, gastrointestinal disorders or alcohol withdrawal syndrome in a patient in need of such treatment or prevention. The methods generally comprise administering to a subject in need of such treatment or prevention a therapeutically effective amount of a pharmaceutical composition of the invention.

• (i) eine maximale Konzentration von H-G im Plasma (Cm) von mindestens 120% der C_max von H-G im Plasma, die durch kolonisches Verabreichen einer äquimolaren Dosis von H-G erreicht wird; und
• (ii) einen AUC-Wert, der mindestens 120% des AUC-Werts ist, der durch kolonisches Verabreichen einer äquimolaren Dosis von H-G erreicht wird,

zu erzeugen.Also described herein is a derivative compound of a GABA analog, MG, for administration to a patient in need of therapy, where M is a pro-unit and G is derived from a GABA analog, HG (where H is hydrogen). The pro-unit M cleaved once from G and any metabolite thereof shows a carcinogen toxic dose (TD ₅₀ ) in rats greater than 0.2 mmol / kg / day. Further, the rat pro-unit M secretes from G in vivo at a sufficient rate in vivo after colon administration to rats to:

• (i) a maximum concentration of HG in the plasma (Cm) of at least 120% of the C _max of HG in the plasma achieved by colonizing an equimolar dose of HG; and
• (ii) an AUC value that is at least 120% of the AUC value achieved by colonically administering an equimolar dose of HG,

to create.

oder ein pharmazeutisch verträgliches Salz, Hydrat oder Solvat davon, wobei:
R Wasserstoff ist oder R und R⁶ zusammen mit den Atomen, an die sie gebunden sind, einen Azetidin-, substituierten Azetidin-, Pyrrolidin- oder substituierten Pyrrolidinring bilden und
Y, R³, R⁴, R⁵, R⁶ und R⁷ wie vorstehend definiert sind.Preferably, MG is a derivative of formula (XIV):

or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
R is hydrogen or R and R ⁶ together with the atoms to which they are attached form an azetidine, substituted azetidine, pyrrolidine or substituted pyrrolidine ring and
Y, R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 are} as defined above.

wobei
n, X, R¹ und R² wie vorstehend definiert sind.Most preferably, M is a derivative of formula (XV):

in which
n, X, R ¹ and R ^{2 are} as defined above.

4. Detailed description of the invention

4.1 Definitions

• a) direkt oder indirekt von einem energievermittelten Prozess abhängt (d. h. durch ATP-Hydrolyse, Ionengradienten, usw. angetrieben wird); oder
• b) durch erleichterte Diffusion auftritt, die durch Wechselwirkung mit speziellen Transportproteinen vermittelt wird.

"Active transport or active transport process" refers to the movement of molecules across cell membranes that:

• a) depends directly or indirectly on an energy-mediated process (ie is driven by ATP hydrolysis, ion gradients, etc.); or
• b) by facilitated diffusion mediated by interaction with specific transport proteins.

"Alkyl" refers to a saturated or unsaturated, branched, straight-chain or cyclic monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne. Typical alkyl radicals include methyl, ethyl radicals such as ethanyl, ethenyl, ethynyl, propyl radicals such as propan-1-yl, propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-ene -2-yl, prop-2-en-1-yl (allyl), cycloprop-1-en-1-yl, cycloprop-2-en-1-yl, prop-1-yn-1-yl, propyl 2-yn-1-yl, etc., butyl radicals, such as butan-1-yl, butan-2-yl, 2-methylpropan-1-yl, 2-methylpropan-2-yl, cyclobutan-1-yl, butyryl 1-en-1-yl, but-1-en-2-yl, 2-methylprop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, Buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3- dien-1-yl, but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc. and the like, but are not limited thereto.

The term "alkyl" is specifically intended to include radicals having any degree of saturation or proportion, i. H. Radicals which have exclusively carbon-carbon single bonds, radicals which have one or more carbon-carbon double bonds, radicals which have one or more carbon-carbon triple bonds, and radicals which contain mixtures of carbon-carbon single bonds, Have double and triple bonds. Where a particular saturation level is provided, the terms "alkanyl", "alkenyl" and "alkynyl" are used. Preferably, an alkyl group comprises 1 to 20 carbon atoms, more preferably 1 to 10 carbon atoms.

"Alkanyl" refers to a saturated branched, straight-chain or cyclic alkyl radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Typical alkanyl radicals include methanyl, ethanyl, propanyl radicals such as propan-1-yl, propan-2-yl (isopropyl), cyclopropan-1-yl, etc., butanyl radicals such as butan-1-yl, butan-2-yl (sec Butyl), 2-methylpropan-1-yl (isobutyl), 2-methylpropan-2-yl (t-butyl), cyclobutan-1-yl, etc. and the like, but are not limited thereto.

"Alkenyl" refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon double bond derived by removal of a hydrogen atom from a single carbon atom of a parent alkene. The remainder may be present either in the cis or trans conformation on the double bond (s). Typical alkenyl radicals include ethenyl, propenyl radicals such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl , Cycloprop-1-en-1-yl, cycloprop-2-en-1-yl, butenyl radicals such as but-1-en-1-yl, but-1-en-2-yl, 2-methylprop-1 en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta- 1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc., and the like, but are not limited to this.

"Alkynyl" refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon triple bond derived by removal of a hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl radicals include ethynyl, propynyl radicals such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc., butynyl radicals such as but-1-yn-1-yl, but-1-in. 3-yl, but-3-yn-1-yl, etc. and the like, but are not limited thereto.

"Acyl" refers to a radical -C (O) R, where R is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, and the like.

"Acylamino" (or in another embodiment "acylamido") refers to a radical -NR'C (O) R where R 'and R are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl , as defined here, are. To conclude representative examples. Formylamino, acetylamino (i.e., acetamido), cyclohexylcarbonylamino, cyclohexylmethylcarbonylamino, benzoylamino (i.e., benzamido), benzylcarbonylamino, and the like, but are not limited thereto.

"Acyloxy" refers to a radical -OC (O) R where R is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl or heteroarylalkyl as defined herein. Representative examples include, but are not limited to, acetyloxy (or acetoxy), butyloxy (or butoxy), benzoyloxy, and the like.

"Alkylamino" means a radical -NHR where R is an alkyl or cycloalkyl radical as defined herein. Representative examples include, but are not limited to, methylamino, ethylamino, 1-methylethylamino, cyclohexylamino, and the like.

"Alkoxy" refers to a radical -OR where R represents an alkyl or cycloalkyl radical as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy, and the like.

"Alkoxycarbonyl" refers to a radical -C (O) alkoxy, where alkoxy is as defined herein.

"Alkylsulfonyl" refers to a radical -S (O) ₂ R where R is an alkyl or cycloalkyl radical as defined herein. Representative examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, and the like.

"Alkylsulfinyl" refers to a group -S (O) R where R is an alkyl or cycloalkyl group as defined herein. Representative examples include, but are not limited to, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, and the like.

"Alkylthio" refers to a radical -SR where R is an alkyl or cycloalkyl radical as defined herein which may optionally be substituted as defined herein. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio and the like.

"Amino" refers to the radical -NH ₂ .

"Aryl" refers to a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of an aromatic parent ring system. Typical aryl radicals include radicals derived from aceanthrens, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalen, as-indacene, s-indacene, indane, indene, naphthalene, octacene, Octaphene, octalen, ovals, penta-2,4-diene, pentacene, pentalen, pentaphene, perylene, phenalen, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like, but are not limited thereto. Preferably, an aryl group comprises 6 to 20 carbon atoms, more preferably between 6 and 12 carbon atoms.

"Arylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp ³ carbon atom, is replaced by an aryl radical. Typical arylalkyl radicals include benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethane-1-yl and the like but not limited to. Where specific alkyl moieties are provided, the nomenclature arylalkanyl, arylalkenyl and / or arylalkynyl is used. Preferably, an arylalkyl radical is (C ₆ -C ₃₀ ) -arylalkyl, e.g. The alkanyl, alkenyl or alkynyl moiety of the arylalkyl group (C ₁ -C ₁₀ ) and is the aryl moiety (C ₆ -C ₂₀ ), more preferably an arylalkyl group (C ₆ -C ₂₀ ) arylalkyl, e.g. The alkanyl, alkenyl or alkynyl moiety of the arylalkyl radical (C ₁ -C ₈ ) and is the aryl moiety (C ₆ -C ₁₂ ).

"Arylalkyloxy" refers to an -O-arylalkyl radical, where arylalkyl is as defined herein.

"Aryloxycarbonyl" refers to a radical -C (O) -O-aryl, where aryl is as defined herein.

"AUC" is the area under the plasma drug concentration-time curve, extrapolated from time zero to infinity.

ausgewählt ist,
wobei:
A(CR³⁵R³⁶)_b ist;
R³⁵ und R³⁶ unabhängig voneinander aus Wasserstoff und Methyl ausgewählt sind;
R³³ und R³⁴ unabhängig voneinander aus Wasserstoff und Methyl ausgewählt sind;
b eine ganze Zahl von 1 bis 4 ist und
c eine ganze Zahl von 0 bis 2 ist."Bridged cycloalkyl" refers to a group consisting of

is selected,
in which:
A is (CR ³⁵ R ³⁶ ) _b ;
R are selected from hydrogen and methyl, independently of one another ³⁵ and R ^36;
R ³³ and R ^{34 are} independently selected from hydrogen and methyl;
b is an integer from 1 to 4 and
c is an integer from 0 to 2.

"Carbamoyl" refers to the radical -C (O) N (R) ₂ where each R independently is hydrogen, alkyl, cycloalkyl or aryl as defined herein which may optionally be substituted as defined herein.

"Carboxy" means the radical -C (O) OH.

"Carcinogenicity Efficacy (TD ₅₀ )" (see Peto et al., Environmental Health Perspectives 1984, 58, 1-8) is defined for a particular compound in a given species as the chronic dose rate in mg / kg body weight / day which in half of the animals would cause tumors at the end of a normal life span for the species. Since the tumor (s) of interest often occur in control animals, TD _{50 is} more accurately defined as the dose rate in mg / kg body weight / day that will halve the likelihood of remaining tumor-free throughout the period, if administered chronically over the normal life span of the species. A TD ₅₀ value can be calculated for any particular neoplasia type, for any particular tissue, or for any combination of these.

" _Cmax " is the highest drug concentration observed in the plasma following an extravascular drug dose.

"Compounds of the invention" refers to compounds encompassed by the claims appended hereto. The compounds of the invention can be identified either by their chemical structure and / or their chemical names. When the chemical structure and its chemical name conflict, the chemical structure determines the identity of the compound. The compounds of the invention may contain one or more chiral centers and / or double bonds and may therefore exist as stereoisomers such as double bond isomers (ie geometric isomers), enantiomers or diastereomers. Thus, the compounds encompassed by the appended claims encompass all possible enantiomers and stereoisomers of the illustrated compounds, including the stereosiomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures may be separated into their enantiomeric or stereoisomeric constituents using separation techniques or chiral synthesis methods well known to those skilled in the art. The compounds of the invention may also exist in various tautomeric forms, including the enol form, the keto form, and mixtures thereof. Thus, the chemical structures presented herein include all sorts of tautomeric forms of the illustrated compounds. The compounds of the invention also include isotope-labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl but not limited to. Further, it should be understood that parentheses indicate the point of attachment of the partial structure to the remainder of the molecule when partial structures of the compounds are illustrated.

"Composition of the invention" refers to at least one compound of the invention and a pharmaceutically acceptable vehicle with which the compound is administered to a patient. When administered to a patient, the compounds of the invention are administered in isolated form, meaning that they are separated from a synthetic organic reaction mixture.

"Cyan" means the radical -CN.

"Cycloalkyl" refers to a saturated or unsaturated cyclic alkyl radical. Where a particular saturation level is provided, the nomenclature "cycloalkanyl" or "cycloalkenyl" is used. Typical cycloalkyl radicals include, but are not limited to, radicals derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like. Preferably, the cycloalkyl radical is (C ₃ -C ₁₀ ) cycloalkyl, more preferably (C ₃ -C ₇ ) cycloalkyl.

"Cycloheteroalkyl" refers to a saturated or unsaturated cyclic alkyl radical in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced by the same or a different heteroatom. Typical heteroatoms for replacing the carbon atom or carbon atoms include, but are not limited to, N, P, O, S, Si, etc. Where a particular level of saturation is provided, the nomenclature "cycloheteroalkanyl" or "cycloheteroalkenyl" is used. Typical cycloheteroalkyl radicals include, but are not limited to, radicals derived from epoxides, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, and the like.

"Cycloheteroalkyloxycarbonyl" refers to a radical -C (O) -OR where R is cycloheteroalkyl as defined herein.

wobei D, E und F jeweils unabhängig voneinander H oder OH sind."Derived from a bile acid" refers to a moiety structurally related to a compound of formulas (XVII) or (XVIII):

wherein D, E and F are each independently H or OH.

The structure of the unit is identical to the above compounds except at positions 1 or 2. At these positions, a hydrogen atom attached to a hydroxyl group and / or the hydroxyl moiety of the carboxylic acid group has been replaced by a covalent bond which serves as a point of attachment to another moiety, which is preferably a GABA analog or GABA analogue derivative.

"Derived from a GABA analog" refers to a moiety structurally related to a GABA analog. The structure of the unit is identical to the connection except at positions 1 or 2. At these positions, a hydrogen atom attached to the amino group and (optionally) the hydroxyl moiety of the carboxylic acid group has been replaced by a covalent bond serving as a point of attachment to another moiety.

"Dialkylamino" means a radical -NRR 'where R and R' independently represent an alkyl or cycloalkyl radical as defined herein. Representative examples include, but are not limited to, dimethylamino, methylethylamino, di (1-methylethyl) amino, (cyclohexyl) (methyl) amino, (cyclohexyl) (ethyl) amino, (cyclohexyl) (propyl) amino, and the like.

wobei:
R Wasserstoff ist oder R und R⁶ zusammen mit den Atomen, an die sie gebunden sind, einen Azetidin-, substituierten Azetidin-, Pyrrolidin- oder substituierten Pyrrolidinring bilden;
R³ und R⁶ unabhängig voneinander aus Wasserstoff, Alkyl, substituiertem Alkyl, Aryl, substituiertem Aryl, Arylalkyl, substituiertem Arylalkyl, Cycloalkyl, substituiertem Cycloalkyl, Cycloheteroalkyl, substituiertem Cycloheteroalkyl. Heteroaryl, substituiertem Heteroaryl, Heteroarylalkyl und substituiertem Heteroarylalkyl ausgewählt sind; und
R⁴ und R⁵ unabhängig voneinander aus Wasserstoff, Alkyl, substituiertem Alkyl, Acyl, substituiertem Acyl, Aryl, substituiertem Aryl, Arylalkyl, substituiertem Arylalkyl, Cycloalkyl, substituiertem Cycloalkyl, Cycloheteroalkyl, substituiertem Cycloheteroalkyl, Heteroaryl, substituiertem Heteroaryl, Heteroarylalkyl und substituiertem Heteroarylalkyl ausgewählt sind oder gegebenenfalls R⁴ und R⁵ zusammen mit dem Kohlenstoffatom, an das sie gebunden sind, einen Cycloalkyl-, substituierten Cycloalkyl-, Cycloheteroalkyl-, substituierten Cycloheteroalkyl- oder verbrückten Cycloalkylring bilden. "GABA analog" refers to a compound which, unless otherwise indicated, has the structure:

in which:
R is hydrogen or R and R ⁶ together with the atoms to which they are attached form an azetidine, substituted azetidine, pyrrolidine or substituted pyrrolidine ring;
R ³ and R ^{6 are} independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl. Heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl; and
R ⁴ and R ^{5 are} independently selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl or optionally R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl or bridged cycloalkyl ring.

"Halogen" means fluorine, chlorine, bromine or iodine.

"Heteroalkyloxy" means an -O-heteroalkyl radical where heteroalkyl is as defined herein.

"Heteroalkyl, heteroalkanyl, heteroalkenyl, heteroalkynyl" refers to an alkyl, alkanyl, alkenyl, or alkynyl radical in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced by the same or different heteroatom radicals. Typical radicals of heteroatoms include -O-, -S-, -OO-, -SS-, -OS-, -NR'-, = NN =, -N = N-, -N = N-NR'-, - PH-, -P (O) ₂ -, -OP (O) ₂ -, -S (O) -, -S (O) ₂ -, -SnH ₂ - and the like, where R 'is hydrogen, alkyl, substituted alkyl , Cycloalkyl, substituted cycloalkyl, aryl or substituted aryl, but are not limited thereto.

"Heteroaryl" refers to a monovalent heteroaromatic radical derived by the removal of a hydrogen atom from a single atom of a heteroaromatic parent ring system. Typical heteroaryl radicals include radicals derived from acridine, arsindole, carbazole, β-carboline, chroman, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromes, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine , Oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene , Triazole, xanthene and the like, but are not limited thereto. Preferably, the heteroaryl group is between 5- and 20-membered heteroaryl, more preferably between 5- and 10-membered heteroaryl. Preferred heteroaryl radicals are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.

"Heteroaryloxycarbonyl" refers to a group -C (O) -OR where R is heteroaryl as defined herein.

"Heteroarylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp ³ carbon atom, is replaced by a heteroaryl radical. Where specific alkyl moieties are provided, the nomenclature heteroarylalkanyl, heteroarylalkenyl and / or heterorylalkynyl is used. In preferred embodiments, the heteroarylalkyl is 6-30 membered heteroarylalkyl, e.g. For example, the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is 1-10 membered and the heteroaryl moiety is 5-20 membered heteroaryl, more preferably 6-20 membered heteroarylalkyl, e.g. For example, the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is 1-8 membered and the heteroaryl moiety is 5-12 membered heteroaryl.

"Passive diffusion" refers to the uptake of an agent that is not mediated by a specific transport protein. An agent that is substantially unable to passively diffuse has a permeability in vitro across a normal cell monolayer (e.g., Caco-2) of less than 5 x 10 ^-6 cm / sec, and usually less than 1 x 10 ^-6 cm / sec (in the absence of an efflux mechanism).

"Pharmaceutically acceptable" means approved or permitted for use in animals, and more particularly in humans, by a state or provincial regulatory agency or listed in the US Pharmacopoeia or other generally recognized pharmacopeia.

"Pharmaceutically acceptable salt" refers to a salt of a compound described herein which is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and the like, or with organic acids such as acetic, propionic, hexanoic, cyclopentanopropionic, glycolic, pyruvic, lactic, Malonic, succinic, malic, maleic, fumaric, tartaric, citric, benzoic, 3- (4-hydroxybenzoyl) benzoic, cinnamic, mandelic, methanesulfonic, ethanesulfonic, 1,2-ethanedisulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic, 2 Naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary-butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid , Muconic acid and the like are formed; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g. An alkali metal ion, an alkaline earth metal ion or an aluminum ion, or is coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like.

"Pharmaceutically acceptable vehicle" refers to a diluent, adjuvant, excipient or carrier to which a compound of the invention is administered.

"Patient" includes humans. The terms "human" and "patient" are used synonymously here.

"Prevention" or "prevention" refers to reducing the risk of acquiring a disease or condition (ie, causing at least one of the clinical symptoms of the condition to be present in a patient susceptible to or susceptible to the disease, but no symptoms the disease perceives or shows, not developed).

"Prodrug" refers to a derivative of a drug molecule that requires conversion in the body to release the active drug. Prodrugs are often (but not necessarily) pharmacologically ineffective until converted to the parent drug.

"Prounite" refers to a form of protecting group that converts the drug into a prodrug when used to mask a functional group in a drug molecule. Typically, the pro-unit will be bound to the drug via binding (s) cleaved in vivo by enzymatic or non-enzymatic means.

"Protecting group" refers to a grouping of atoms that masks, reduces or prevents the reactivity of the functional group when attached to a reactive functional group in a molecule. Examples of protecting groups can be found in Greene et al., Protective Groups in Organic Chemistry, (Wiley, 2nd Ed., 1991) and Harrison et al., Compendium of Synthetic Organic Methods, Volumes 1-8 (John Wiley et al Sons, 1971-1996). Representative amino protecting groups include formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilylethanesulfonyl ("SES"), trityl, and substituted trityl residues, allyloxycarbonyl , 9-fluorenylmethyloxycarbonyl ("FMOC"), nitroveratryloxycarbonyl ("NVOC") and the like, but are not limited thereto. Representative hydroxy protecting groups include but are not limited to those where the hydroxy group is either acylated or alkylated, such as benzyl and trityl ethers, and alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers, and allyl ethers.

"Substituted" refers to a radical in which one or more hydrogen atoms are each independently replaced by the same or different substituents. Typical substituents include -X, -R ^29, -O ^-, = O, -OR ^29, -SR ^29, -S ^-, -NR ²⁹ R ^30, = NR ^29, -CX _3, -CF _3, -CN, -OCN, -SCN, -NO, -NO _2, = N _2, -N _3, -S (O) ₂ O ^-, S (O) ₂ OH, -S (O) ₂ R ^29, -OS (O ₂ ) O-, -OS (O) ₂ R ²⁹ , -P (O) (O) ₂ , -P (O) (OR ²⁹ ) (O ^- ), -OP (O) (OR ²⁹ ) (OR ³⁰ ), -C (O) R ²⁹ , -C (S) R ²⁹ , -C (O) OR ²⁹ , -C (O) NR ²⁹ R ³⁰ , -C (O) O ^- , -C (S) OR ²⁹ , -NR ³¹ C (O) NR ²⁹ R ³⁰ , -NR ³¹ C (S) NR ²⁹ R ³⁰ , -NR ³¹ C (NR ²⁹ ) NR ²⁹ R ³⁴ and -C (NR ²⁹ ) NR ²⁹ R ³⁰ , where each X is independently a halogen atom, R ²⁹ and R ³⁰ each independently is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, -NR ³¹ R ³² , -C (O) R ³¹ or -S (O) ₂ R ³¹ or R ²⁹ and R ³⁰ optionally together with the atom to which they are both attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring, and R ³¹ and R ³² are each independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, but are not limited to this.

"Transport protein" refers to a protein that has a direct or indirect role in transporting a molecule into and / or through a cell. For example, a transport protein can provide carrier transporters for solutes, cotransporters, counterproducts, uniport, symporter, antiporter, pump, equilibration-targeted transporters, concentration-targeted transporters, and other proteins that mediate active transport, energy-dependent transport, facilitated diffusion, exchange mechanisms, and specific absorption mechanisms be, but not limited to. Transport proteins may also be, but are not limited to, membrane-bound proteins that recognize a substance and cause it to enter or exit a cell through a carrier-mediated transporter or through receptor-mediated transport. A transport protein may also be, but is not limited to, an intracellularly expressed protein involved in trafficking of substances through a cell or from a cell. Transport proteins can also bind proteins or glycoproteins exposed on the surface of a cell that do not directly transport a substance, but are held to the substance while being held near a receptor or transport protein that causes the substance to enter or through the cell be, but are not limited to. Examples of carrier proteins include the intestinal and liver bile acid transporters, dipeptide transporters, oligopeptide transporters, simple sugar transporters (eg SGLTI), phosphate transporters, monocarboxylic acid transporters, P-glycoprotein transporters, organic anionic transporters. Transporter (OAT) and organic cation transporters. Examples of receptor-mediated transport proteins include viral receptors, immunoglobulin receptors, bacterial toxin receptors, plant lectin receptors, bacterial adhesion receptors, vitamin transporters, and cytokine growth factor receptors.

"Treating" or "treating" any disease or disease in one embodiment relates to improving the disease or condition (i.e., arresting or reducing the development of the disease, or at least one of the clinical symptoms thereof). In another embodiment, "treating" or "treating" refers to improving at least one physical parameter that may be imperceptible to the patient. In yet another embodiment, "treating" or "treating" refers to inhibiting the disease or condition either physically (eg, stabilization of a noticeable symptom), physiologically (eg, stabilization of a physical parameter), or both. In yet another embodiment, "treating" or "treating" refers to delaying the onset of the disease or condition.

"Therapeutically effective amount" means the amount of a compound that, when administered to a patient for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc. of the patient being treated.

Now, reference will be made in detail to preferred embodiments of the invention. Although the invention will be described in conjunction with the preferred embodiments, it will be understood that it is not intended to limit the invention to these preferred embodiments.

4.2 The connections

Those skilled in the art will recognize that compounds of formulas (I), (II) and (III) share certain structural features together. These compounds are all GABA analogs (ie γ-aminobutyric acid derivatives) to which pro units have been attached. In particular, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X and Y are common substituents found in compounds of formulas (I), (II) and (III).

oder ein pharmazeutisch verträgliches Salz, Hydrat oder Solvat davon beschrieben, wobei:
n, t, u, X, Y, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ R²⁰, R²¹, R²² und R²³ wie vorher vorstehend definiert sind.Here are compounds of formula (I), formula (II) or formula (III):

or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
n, t, u, X, Y, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ R ²⁰ , R ²¹ , R ²² and R ^{23 are} as previously defined above.

In a preferred embodiment, compounds of formulas (I), (II) and (III) do not include the following compounds:
when R ³ and R ^{6 are} both hydrogen, then R ⁴ and R ^{5 are} not both hydrogen and not both methyl;
when in a compound of formula (I) either n is 0 or when n is 1 and X is NR ¹⁶ , then R ^{1 is} not hydrogen;
in a compound of formula (I), neither R ¹ , R ⁷ O-, R ²⁴ C (O) -, R ²⁵ C (O) - nor R ²⁵ O- is a unit derived from a bile acid;
when in a compound of formula (I) R ¹ R ^{24 is} C (O) - and n is 0 then R ^{24 is} not methyl, tert -butyl, 2-aminoethyl, 3-aminopropyl, benzyl, phenyl or 2- (benzoyloxymethyl) phenyl;
when in a compound of formula (I) R ¹ R ^{25 is} OC (O) -, then R ^{25 is} not R ²⁶ C (O) CR ¹³ R ¹⁴ -, wherein R ^{26 is selected} from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl;
when in a compound of formula (I) R ¹ R ^{25 is} OC (O) - and n is 0 then R ^{25 is} not methyl, tert -butyl or benzyl;
when in a compound of formula (I) n is 0 and R ¹ R ^{25 is} C (O) OCR ^{1 3} R ¹⁴ OC (O) -, then, if either R ³³ or R ^{14 is} hydrogen, alkoxycarbonyl, substituted alkoxycarbonyl, Carbamoyl, cycloalkoxycarbonyl or substituted cycloalkoxycarbonyl, the other radical R ¹³ or R ^{14 is} not hydrogen;
when in a compound of formula (I) n is 1, X is NH, R ³ , R ⁵ and R ^{6 are} each hydrogen and R ^{4 is} cyclohexyl, then R ^{2 is} not benzyl;
when in a compound of formula (II) t is 1 and u is 0, then neither R ²⁰ nor R ^{21 is} 2-hydroxy-3-methyl-5-chlorophenyl; and
when in a compound of formula (II) u is 1 and X is O, then t is 1.

In one embodiment of the compounds of formulas (I), (II) and (III), when R ³ and R ^{6 are} each hydrogen, then R ⁴ and R ^{5 are} neither both hydrogen nor both methyl. In one embodiment of the compounds of formula (I), when either n is 0 or when n is 1 and X is NR ¹⁶ , then R ^{1 is} not hydrogen. In another embodiment of the compounds of formula (I), neither R ¹ , R ⁷ O-, R ²⁴ C (O) -, R ²⁵ C (O) nor R ²⁵ O- is a unit derived from a bile acid , In yet another embodiment of the compounds of formula (I) when R ^{1 is} R ²⁴ C (O) - and n is 0, then R ^{24 is} not alkyl, substituted alkyl, arylalkyl, aryl or substituted aryl. In yet another embodiment of the compounds of formula (I) when R ^{1 is} R ²⁴ C (O) - and n is 0, then R ^{24 is} not C _1-4 alkanyl, benzyl, phenyl or substituted phenyl. In yet another embodiment of the compounds of formula (I) when R ^{1 is} R ²⁴ C (O) - and n is 0, then R ^{24 is} not methyl, tert -butyl, 2-aminoethyl, 3-aminopropyl, benzyl, Phenyl or 2- (benzoyloxymethyl) phenyl. In yet another embodiment of the compounds of formula (I) R ¹ R ^{25 is} OC (O) -, then R ^{25 is} not R ²⁶ C (O) CR ¹³ R ¹⁴ -. In yet another embodiment of the compounds of formula (I) when R ¹ R ^{25 is} OC (O) - and n is 0 then R ^{25 is} not alkyl or arylalkyl. In yet another embodiment of the compounds of formula (I) when R ¹ R ^{25 is} OC (O) - and n is 0 then R ^{25 is} not C _1-4 alkanyl or benzyl. In yet another embodiment of the compounds of formula (I) when R ¹ R ^{25 is} OC (O) - and n is 0, then R ^{25 is} not methyl, tert-butyl or benzyl. In yet another embodiment, when the compounds of formula (I) n is 0 and R ^{1 is} R ²⁵ C (O) OCR ¹³ R ¹⁴ OC (O) -, then, if either R ¹³ or R ^{14 is} hydrogen, alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl, cycloalkoxycarbonyl or substituted cycloalkoxycarbonyl, the other radical R ¹³ or R ^{14 is} not hydrogen. In yet another embodiment of the compounds of formula (I), R ³ , R ⁵ and R ^{6 are} each hydrogen, then R ^{4 is} not cyclohexyl. In yet another embodiment of the compounds of formula (I) n is 1, X is NH, R ³ , R ⁵ , R ^{6 are} each hydrogen and R ^{2 is} benzyl, then R ^{4 is} not cyclohexyl.

In one embodiment of the compounds of the formula (II), neither R ²⁰ nor R ^{21 is} 2-hydroxy-3-methyl-5-chlorophenyl. In one embodiment of the compounds of formula (II), when u is 1 and X is O, then t is 1.

In one embodiment of the compounds of formulas (I), (II) and (III) n is 0. In another embodiment, n is 1. When n is 1 and X is NR ¹⁶ , the α-amino acid preferably has the stereochemical L- Configuration on.

wo V O oder CH₂ ist.In another embodiment of the compounds of formulas (I) and (II), R ^{7 is selected} from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, substituted cycloalkanyl, cycloheteroalkanyl and substituted cycloheteroalkanyl. In a preferred embodiment, YO and R ⁷ is hydrogen. In yet another embodiment, Y is O and R ⁷ is alkanyl, substituted alkanyl, alkenyl, substituted alkenyl, aryl or substituted aryl. Preferably R ^{7 is} methyl, ethyl, benzyl, -C (CH ₃ ) = CH ₂ , -CH ₂ C (O) N (CH ₃ ) ₂ ,

where V is O or CH ₂ .

In a preferred embodiment of the compounds of the formulas (I), (II) and (III) R ^{2 is} hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, Heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl. Preferably, R ^{2 is selected} from hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkyl and substituted heteroarylalkanyl.

In another embodiment of the compounds of formulas (I), (II) and (III) X is NH and R ² is hydrogen, cycloalkanyl or alkanyl. Preferably, R ^{2 is} hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl or cyclohexyl. In another embodiment, X is NH and R ² is substituted alkanyl. Preferably, R ^{2 is} -CH ₂ OH, -CH (OH) CH ₃ , -CH ₂ CO ₂ H, -CH ₂ CH ₂ CO ₂ H, -CH ₂ CONH ₂ , -CH ₂ CH ₂ CONH ₂ , -CH ₂ CH ₂ SCH ₃ , -CH ₂ SH, -CH ₂ (CH ₂ ) ₃ NH ₂ or -CH ₂ CH ₂ CH ₂ NHC (NH) NH ₂ . In yet another embodiment, X is NH and R ² is selected from aryl, arylalkanyl, substituted arylalkanyl and heteroarylalkanyl. Preferably, R ^{2 is} phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl or 2-indolyl. In yet another embodiment, X is NR ¹⁶ and R ² and R ¹⁶ together with the atoms to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring. Preferably, R ² and R ¹⁶ together with the atoms to which they are attached form an azetidine, pyrrolidine or piperidine ring.

In yet another embodiment of the compounds of formulas (I), (II) and (III), R ^{3 is} hydrogen. In yet another embodiment, R ^{6 is} hydrogen. In yet another embodiment R ³ and R ^{6 are} independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl and substituted cycloalkyl. Preferably, R ³ and R ^{6 are} independently selected from hydrogen and alkanyl. More preferably R ^{3 is} hydrogen or alkanyl and R ⁶ is hydrogen.

In still another preferred embodiment of the compounds of formulas (I), (II) and (III), R ⁴ and R ^{5 are} independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl and substituted cycloheteroalkyl. Preferably, R ⁴ and R ^{5 are} independently selected from hydrogen, alkanyl and substituted alkanyl.

In another embodiment of the compounds of formulas (I), (II) and (III), R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cycloalkanyl or substituted cycloalkanyl ring. Preferably, R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, cyclohexyl or substituted cyclohexyl ring. In another embodiment, R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring. In yet another embodiment, R ⁴ and R ⁵ together with the carbon atom to which they are attached form a bridged cycloalkyl ring.

In one embodiment of the compounds of formula (I) n is 1, R ^{1 is} R ²⁴ C (O) - or R ^{24 is} C (S) - and R ^{24 is} alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl , Heteroaryl or substituted heteroaryl. Preferably, R ^{24 is} methyl, ethyl, 2-propyl, t-butyl, -CH ₂ OCH (CH ₃ ) ₂ , phenyl or 3-pyridyl.

In another embodiment of the compounds of formula (I) n is 1, R ^{3 is} R ²⁵ OC (O) - or R ^{25 is} SC (O) - and R ^{25 is} alkyl, substituted alkyl, heteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl. Preferably R ^{25 is} ethyl, 2-propyl, neo-pentyl, -CH ₂ OCH (CH ₃ ) ₂ , phenyl or 2-pyridyl.

oder ein pharmazeutisch verträgliches Salz, Hydrat oder Solvat davon ein, wobei:
n, Y, R², R³, R⁴, R⁵, R⁶, R⁷, R¹³, R¹⁴, R¹⁶ und R²⁵ wie vorstehend definiert sind.A preferred embodiment of the compounds of the formula (I) includes compounds of the formula (IV):

or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
n, Y, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ¹³ , R ¹⁴ , R ¹⁶ and R ^{25 are} as defined above.

In a preferred embodiment, the compounds of formula (IV) do not include the following compounds:
when either R ¹³ or R ^{14 is} hydrogen, alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl, cycloalkoxycarbonyl or substituted cycloalkoxycarbonyl, then the other radical of R ¹³ and R ^{14 is} not hydrogen; and
R ²⁵ C (O) is not a unit derived from a bile acid.

In one embodiment of the compounds of formula (IV), R ¹³ and R ^{14 are} independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, aryl, arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl or heteroaryl (preferably when R ^{13 is} alkoxycarbonyl, cycloalkoxycarbonyl or Carbamoyl, then R ^{14 is} methyl). More preferably R ¹³ and R ^{14 are} independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl or 3-pyridyl.

In another embodiment of the compounds of formula (IV), R ¹³ and R ^{14 are} independently hydrogen, alkanyl, substituted alkanyl, cycloalkanyl or substituted cycloalkanyl. Preferably, R ¹³ and R ^{14 are} hydrogen, alkanyl or cycloalkanyl. More preferably, R ¹³ and R ^{14 are} independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl or cyclohexyl. Even more preferably R ^{33 is} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl or cyclohexyl and R ¹⁴ is hydrogen or R ¹³ is methyl and R ¹⁴ is methyl.

In yet another embodiment of the compounds of formula (IV), R ¹³ and R ^{14 are} independently hydrogen, aryl, arylalkyl or heteroaryl. More preferably, R ¹³ and R ^{14 are} independently hydrogen, phenyl, benzyl, phenethyl or 3-pyridyl. Even more preferred. R ^{13 is} phenyl, benzyl, phenethyl or 3-pyridyl and R ¹⁴ is hydrogen.

In yet another embodiment of the compounds of formula (IV), R ¹³ and R ^{14 are} independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, carbamoyl or cycloalkoxycarbonyl. Preferably when R ^{13 is} alkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl then R ^{14 is} methyl. More preferably R ^{13 is} methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert -butoxycarbonyl or cyclohexyloxycarbonyl, and R ¹⁴ is methyl.

In yet another embodiment of the compounds of formula (IV), R ¹³ and R ¹⁴ together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring. Preferably, R ¹³ and R ¹⁴ together with the carbon atom to which they are attached form a cycloalkyl ring. More preferably R ¹³ and R ¹⁴ together with the carbon atom to which they are attached form a cyclobutyl, cyclopentyl or cyclohexyl ring. In yet another embodiment of the compounds of formula (IV) R ^{25 is} acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, Heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl. Preferably, R ^{25 is} acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl. More preferably R ^{25 is} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) ethyl, 1- (1,3-dioxan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1- (1,3-dioxolan-2-yl) propyl, 1- (1,3-dioxan-2-yl) propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1- (1,3-dioxolan-2-yl) butyl, 1- (1,3 Dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3-dioxolan-2-yl) benzyl, 1- (1,3-dioxan-2-yl) benzyl , 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3-dioxolan-2-yl) -2-phenethyl, 1- (1,3-dioxane-2-) yl) -2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl.

In yet another embodiment of the compounds of formula (IV), R ^{25 is} acyl or substituted acyl. More preferably R ^{25 is} acetyl, propionyl, butyryl, benzoyl or phenacetyl.

In yet another embodiment of the compounds of formula (IV), R ^{25 is} alkanyl or substituted alkanyl. Preferably R ^{25 is} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1- (1,3 Dioxolan-2-yl) ethyl, 1- (1,3-dioxolan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1- (1,3-dioxolan-2-yl) propyl , 1- (1,3-dioxan-2-yl) propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1- (1,3-dioxolan-2-yl) butyl, 1- (1,3- Dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3-dioxolan-2-yl) benzyl, 1- (1,3-dioxan-2-yl) benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3-dioxolan-2-yl) -2-phenethyl or 1- (1,3-dioxan-2-yl ) -2-phenethyl. More preferably R ^{25 is} methyl, ethyl, propyl, isopropyl, butyl, 1,1-dimethoxyethyl or 1,1-diethoxyethyl.

In yet another embodiment of the compounds of formula (IV), R ^{25 is} aryl, arylalkyl or heteroaryl. Preferably, R ^{25 is} phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl.

In yet another embodiment of the compounds of formula (IV), R ^{25 is} cycloalkyl or substituted cycloalkyl. More preferably R ^{25 is} cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In yet another embodiment of the compounds of formula (IV) R ^{25 is} acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, Heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl and R ¹³ and R ¹⁴ are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted Cycloalkoxycarbonyl, heteroaryl or substituted heteroaryl (preferably when R ^{13 is} alkoxycarbonyl, substituted alkoxycarbonyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl or carbamoyl, then R ^{14 is} methyl). Preferably R ^{25 is} acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl and R ¹³ and R ¹⁴ are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, aryl, arylalkyl, carbamoyl, cycloalkyl, cycloalkoxycarbonyl or heteroaryl (preferably when R ^{13 is} alkoxycarbonyl, substituted alkoxycarbonyl, cycloalkoxycarbonyl is substituted cycloalkoxycarbonyl or carbamoyl, then R ^{14 is} methyl). More preferably R ^{25 is} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) ethyl, 1- (1,3-dioxan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1- (1,3-dioxolan-2-yl) propyl, 1- (1,3-dioxan-2-yl) propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1- (1,3-dioxolan-2-yl) butyl, 1- (1,3 Dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3-dioxolan-2-yl) benzyl, 1- (1,3-dioxan-2-yl) benzyl , 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3-dioxolan-2-yl) -2-phenethyl, 1- (1,3-dioxane-2-) yl) -2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl, and R ¹³ and R ¹⁴ are independently hydrogen , Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, methoxycarbonyl, ethoxycarbonyl, propox ycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl or 3-pyridyl. Even more preferably, R ^{25 is} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1,1 -Dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, cyclohexyl or 3-pyridyl; and R ¹³ and R ¹⁴ are independently from each other hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl or 3-pyridyl.

In yet another embodiment of the compounds of formula (IV) R ^{25 is} acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, Heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl and R ¹³ and R ¹⁴ together with the atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring. Preferably R ^{25 is} acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl, and R ¹³ and R ¹⁴ together with the atom to which they are attached form a cycloalkyl or substituted cycloalkyl ring. More preferably R ^{25 is} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) ethyl, 1- (1,3-dioxan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1- (1,3-dioxolan-2-yl) propyl, 1- (1,3-dioxan-2-yl) propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1- (1,3-dioxolan-2-yl) butyl, 1- (1,3 Dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3-dioxolan-2-yl) benzyl, 1- (1,3-dioxan-2-yl) benzyl , 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3-dioxolan-2-yl) -2-phenethyl, 1- (1,3-dioxane-2-) yl) -2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl and R ¹³ and R ¹⁴ form together with the Atom to which they are attached, a cyclobutyl, cyclopentyl or a cyclohexyl ring.

In yet another embodiment of the compounds of formula (IV) R ^{25 is} acyl or substituted acyl and R ¹³ and R ¹⁴ are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, Carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl or substituted heteroaryl (preferably when R ^{13 is} alkoxycarbonyl, substituted alkoxycarbonyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl or carbamoyl, then R ^{14 is} methyl). Preferably R ^{25 is} acetyl, propionyl, butyryl, benzoyl or phenacetyl and R ¹³ and R ¹⁴ are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl , Cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl or substituted heteroaryl (preferably when R ^{13 is} alkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl then R ^{14 is} methyl.

In yet another embodiment of the compounds of formula (IV) R ^{25 is} alkanyl or substituted alkanyl and R ¹³ and R ¹⁴ are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, Carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl or substituted heteroaryl (preferably when R ^{13 is} alkoxycarbonyl, substituted alkoxycarbonyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl or carbamoyl, then R ^{14 is} methyl). Preferably R ^{25 is} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1- (1,3 Dioxolan-2-yl) ethyl, 1- (1,3-dioxan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1-Diethoxypropyl, 1- (1,3-dioxolan-2-yl) -propyl, 1- (1,3-dioxan-2-yl) -propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1 - (1,3-dioxolan-2-yl) butyl, 1- (1,3-dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3-dioxolane 2-yl) benzyl, 1- (1,3-dioxan-2-yl) benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3-dioxolane 2-yl) -2-phenethyl or 1- (1,3-dioxan-2-yl) -2-phenethyl and R ¹³ and R ¹⁴ are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted Aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl or substituted heteroaryl (preferably when R ^{13 is} alkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl, then R ^{14 is} methyl).

In yet another embodiment of the compounds of formula (IV) R ^{25 is} aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl or substituted heteroaryl and R ¹³ and R ¹⁴ are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, Aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl or substituted heteroaryl (preferably when R ^{13 is} alkoxycarbonyl, substituted alkoxycarbonyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl or carbamoyl then R ^{14 is} methyl) , Preferably R ^{25 is} phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl and R ¹³ and R ¹⁴ are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, Carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl or substituted heteroaryl (preferably when R ^{13 is} alkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl, then R ^{14 is} methyl).

In yet another embodiment of the compounds of formula (IV), R ²⁵ cycloalkyl or substituted cycloalkyl, and R ¹³ and R ^{1 4} are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl , Carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl or substituted heteroaryl (preferably when R ^{13 is} alkoxycarbonyl, substituted alkoxycarbonyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl or carbamoyl, then R ^{14 is} methyl). Preferably R ^{25 is} cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and R ¹³ and R ¹⁴ are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl , substituted cycloalkoxycarbonyl, heteroaryl or substituted heteroaryl (preferably when R ^{13 is} alkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl, then R ^{14 is} methyl).

In another embodiment of the compounds of the formula (IV), R ^{25 is} acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, Heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl and R ³³ and R ¹⁴ are each independently hydrogen, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl. Preferably, R ^{25 is} acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl and R ¹³ and R ¹⁴ are independently hydrogen, alkanyl, substituted alkanyl, cycloalkanyl or substituted cycloalkanyl. More preferably R ^{25 is} acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl and R ¹³ and R ¹⁴ are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl or cyclohexyl. In the above Embodiments R ^{25 is} preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) ethyl, 1- (1,3-dioxan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1- (1,3-dioxolan-2-yl) propyl, 1- (1,3-dioxan-2-yl) propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1- (1,3-dioxolan-2-yl) butyl, 1- (1,3 Dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3-dioxolan-2-yl) benzyl, 1- (1,3-dioxan-2-yl) benzyl , 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3-dioxolan-2-yl) -2-phenethyl, 1- (1,3-dioxane-2-) yl) -2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl.

In yet another embodiment of the compounds of formula (IV) R ^{25 is} acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl and R ¹³ and R ¹⁴ are independently hydrogen, alkyl, substituted alkyl, aryl, Arylalkyl, cycloalkyl or heteroaryl. Preferably, R ^{25 is} acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl and R ¹³ and R ¹⁴ are independently hydrogen, aryl, arylalkyl or heteroaryl. More preferably R ^{25 is} acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl and R ¹³ and R ¹⁴ are independently hydrogen, phenyl, benzyl, phenethyl or 3-pyridyl. In the above embodiments, R ^{25 is} preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1- (1,3-dioxolan-2-yl) ethyl, 1- (1,3-dioxan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1- (1,3-dioxolane-2 -yl) propyl, 1- (1,3-dioxan-2-yl) propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1- (1,3-dioxolan-2-yl) butyl, 1- ( 1,3-dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3-dioxolan-2-yl) benzyl, 1- (1,3-dioxane-2-yl) yl) benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3-dioxolan-2-yl) -2-phenethyl, 1- (1,3-dioxane 2-yl) -2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl.

In yet another embodiment of the compounds of formula (IV) R ^{25 is} acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl and R ¹³ and R ¹⁴ are independently hydrogen, alkyl, substituted alkyl, aryl, Arylalkyl, cycloalkyl or heteroaryl. Preferably R ^{25 is} acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl and R ¹³ and R ¹⁴ are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl, cycloalkoxycarbonyl or substituted cycloalkoxycarbonyl (preferably when R ^{13 is} alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl, cycloalkoxycarbonyl or substituted cycloalkoxycarbonyl, then R ^{14 is} methyl, more preferably R ^{13 is} methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert -butoxycarbonyl or cyclohexyloxycarbonyl and R ¹⁴ is methyl). In the above embodiments, R ^{25 is} preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1- (1,3-dioxolan-2-yl) ethyl, 1- (1,3-dioxan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1- (1,3-dioxolane-2 -yl) propyl, 1- (1,3-dioxan-2-yl) propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1- (1,3-dioxolan-2-yl) butyl, 1- ( 1,3-dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3-dioxolan-2-yl) benzyl, 1- (1,3-dioxane-2-yl) yl) benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3-dioxolan-2-yl) -2-phenethyl, 1- (1,3-dioxane 2-yl) -2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl.

In yet another embodiment of the compounds of formula (IV) R ^{25 is} acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl and R ¹³ and R ¹⁴ together with the atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring. Preferably R ^{25 is} acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl, and R ¹³ and R ¹⁴ together with the atom to which they are attached form a cycloalkyl or substituted cycloalkyl ring. More preferably R ^{25 is} acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl, and R ¹³ and R ¹⁴ together with the atom to which they are attached form a cyclobutyl, cyclopentyl or cyclohexyl ring. In the above embodiments, R ^{25 is} preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1- (1,3-dioxolan-2-yl) ethyl, 1- (1,3-dioxan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1- (1,3-dioxolane-2 -yl) propyl, 1- (1,3-dioxan-2-yl) propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1- (1,3-dioxolan-2-yl) butyl, 1- ( 1,3-dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3-dioxolan-2-yl) benzyl, 1- (1,3-dioxane-2-yl) yl) benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3-dioxolan-2-yl) -2-phenethyl, 1- (1,3-dioxane 2-yl) -2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl.

ist m 0 und sind R⁸, R¹¹ und R¹² wie vorstehend definiert.In yet another embodiment of the compounds of formulas (I) and (III), R ^{1 is}

m is 0 and R ⁸ , R ¹¹ and R ^{12 are} as defined above.

In one embodiment of the compounds of formulas (I) and (III) R ^{11 is} acyl, alkoxycarbonyl, aryloxycarbonyl, cycloalkoxycarbonyl or carbamoyl, R ^{8 is} hydrogen, alkoxycarbonyl, alkyl, aryl, arylalkyl or cyano and R ^{12 is} hydrogen, alkoxycarbonyl, alkyl , substituted alkyl, aryl or arylalkyl.

In another embodiment of the compounds of formulas (I) and (III), R ^{11 is} acetyl, propionyl, butyryl, isobutyryl, pivaloyl, cyclopentanecarbonyl, cyclohexanecarbonyl, benzoyl, phenacetyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec Tert-butoxycarbonyl, tert-butoxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-isobutylcarbamoyl, N-sec-butylcarbamoyl, N-tert-butylcarbamoyl, N-cyclopentylcarbamoyl, N -cyclohexylcarbamoyl, N-phenylcarbamoyl, N -benzylcarbamoyl, N, N -dimethylcarbamoyl, N, N -diethylcarbamoyl, N, N -dipropylcarbamoyl, N, N -diisopropylcarbamoyl, N, N Dibutylcarbamoyl, N, N-dibenzylcarbamoyl, N-pyrrolidinylcarbamoyl, N-piperidinylcarbamoyl and N-morpholinylcarbamoyl. More preferably, R ^{11 is selected} from acetyl, propionyl, butyryl, isobutyryl, cyclohexanecarbonyl, benzoyl, phenacetyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, cyclohexyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, carbamoyl, N -methylcarbamoyl, N -ethylcarbamoyl, N -propylcarbamoyl, N-isopropylcarbamoyl, N-phenylcarbamoyl, N -benzylcarbamoyl, N, N -dimethylcarbamoyl, N, N -diethylcarbamoyl, N, N -dipropylcarbamoyl, N -pyrrolidinylcarbamoyl, N -piperidinylcarbamoyl and N -morpholinylcarbamoyl.

In yet another embodiment of the compounds of formulas (I) and (III), R ^{8 is selected} from hydrogen, methyl, ethyl, propyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl and cyano , More preferably, R ^{8 is selected} from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl.

In yet another embodiment of the compounds of formulas (I) and (III) R ^{12 is selected} from hydrogen, methyl, ethyl, propyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, phenoxycarbonyl and benzyloxycarbonyl. More preferably, R ^{12 is selected} from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl.

In yet another embodiment of the compounds of formulas (I) and (III), R ^{11 is selected} from hydrogen, alkoxycarbonyl, alkyl, substituted alkyl, aryl and arylalkyl and R ⁸ and R ¹² together with the carbon atoms to which they are attached , a cycoalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring. Preferably, R ^{11 is selected} from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl, and R ⁸ and R ¹² together with the carbon atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl - or substituted Cycloheteroalkylring. More preferably R ^{11 is} hydrogen or methyl and R ⁸ and R ¹² , taken together with the carbon atoms to which they are attached, form a cyclopent-1-ene, cyclohex-1-ene, 2-cyclopenten-1-one, 2-cyclohexen-1-one, 2- (5H) -furanone or 5,6-dihydropyran-2-one ring.

In yet another embodiment of the compounds of formulas (I) and (III), R ^{12 is selected} from hydrogen, alkoxycarbonyl, alkyl, substituted alkyl, aryl, and arylalkyl, and R ⁸ and R ¹¹ form together with the carbon atoms to which they are attached , a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring. Preferably, R ^{12 is selected} from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl, and R ⁸ and R ¹¹ together with the carbon atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl - or substituted Cycloheteroalkylring. More preferably, R ^{12 is selected} from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, etoxycarbonyl, and butoxycarbonyl, and R ⁵ and R ¹¹ together with the carbon atoms to which they are attached form a γ-butyrolactone, δ- Valerolactone or 2,2-dimethyl-1,3-dioxane-4,6-dione ring.

und R¹⁵ ist aus Alkyl, substituiertem Alkyl, Cycloalkyl, substituiertem Cycloalkyl, Aryl, substituiertem Aryl, Heteroaryl und substituiertem Heteroaryl ausgewählt. Vorzugsweise ist R¹⁵ Methyl, Ethyl, Propyl, Isopropyl, Cyclopentyl, Cyclohexyl, Phenyl, 4-Hydroxyphenyl, Benzyl, 4-Hydroxybenzyl oder 3-Pyridyl.In yet another embodiment of the compounds of formulas (I) and (III), R ^{1 is}

and R ¹⁵ is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl. Preferably R ^{15 is} methyl, ethyl, propyl, isopropyl, cyclopentyl, cyclohexyl, phenyl, 4-hydroxyphenyl, benzyl, 4-hydroxybenzyl or 3-pyridyl.

wo
R³⁷ Wasserstoff, Alkyl, substituiertes Alkyl, Acyl, Aryl, substituiertes Aryl, Arylalkyl, substituiertes Arylalkyl, Cycloalkyl, Heterocycloalkyl, substituiertes Cycloheteroalkyl, Heteroaryl, substituiertes Heteroaryl, Heteroarylalkyl oder substituiertes Heteroarylalkyl ist;
Z O, N oder S ist und
Ar Aryl, substituiertes Aryl, Heteroaryl oder substituiertes Heteroaryl ist.In still another embodiment of formulas (I) and (III), R ^{1 is}

Where
R ^{37 is} hydrogen, alkyl, substituted alkyl, acyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, heterocycloalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;
ZO, N or S is and
Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl.

Preferably, Z and CH ₂ OC (O) - are in a conjugated relationship to one another (eg, 1,4- or 1,2-linked in a six-membered ring system).

wo
q 0 oder 1 ist;
R³⁸ und R³⁹ unabhängig voneinander Wasserstoff, Alkyl, substituiertes Alkyl, Cycloalkyl, substituiertes Alkyl, Aryl, substituiertes Aryl, Heteroaryl und substituiertes Heteroaryl sind;
R⁴⁰ und R⁴¹ unabhängig voneinander Wasserstoff, Alkyl, substituiertes Alkyl, Cycloalkyl, substituiertes Alkyl, Aryl, substituiertes Aryl, Heteroaryl und substituiertes Heteroaryl sind oder zusammen mit dem Kohlenstoffatom, an das sie gebunden sind, einen Cycloalkylring bilden;
R⁴² und R⁴³ unabhängig voneinander Alkyl, substituiertes Alkyl, Cycloalkyl, substituiertes Alkyl, Aryl, substituiertes Aryl, Heteroaryl und substituiertes Heteroaryl sind oder zusammen mit den Kohlenstoffatomen, an die sie gebunden sind, einen Aryl-, substituierten Aryl-, Heteroaryl- oder substituierten Heteroarylring bilden; und
R³⁷ wie vorstehend definiert ist.In still another embodiment of formulas (I) and (III), R ^{1 is}

Where
q is 0 or 1;
R ³⁸ and R ^{39 are} independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted alkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
R ⁴⁰ and R ^{41 are} independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted alkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl, or together with the carbon atom to which they are attached form a cycloalkyl ring;
R ⁴² and R ^{43 are} independently alkyl, substituted alkyl, cycloalkyl, substituted alkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl, or together with the carbon atoms to which they are attached, an aryl, substituted aryl, heteroaryl or form substituted heteroaryl ring; and
R ^{37 is} as defined above.

In a preferred embodiment of the compounds of formulas (I) - (IV) is YO, R ³ , R ⁶ and R ^{7 are} hydrogen and R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cycloalkyl, substituted Cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, bridged cycloalkyl or substituted bridged cycloalkyl ring. In another preferred embodiment of the compounds of formulas (I) - (IV), R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cycloalkyl or substituted cycloalkyl ring. In one embodiment n is 0, t is 0 and u is 0. In another embodiment, n is 1 and R ^{2 is} hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, t-butyl, cyclopentyl, cyclohexyl, phenyl, Benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 2-indolyl, -CH ₂ OH, -CH (OH) CH ₃ , -CH ₂ CO ₂ H, -CH ₂ CH ₂ CO ₂ H, -CH ₂ CONH ₂ , -CH ₂ CH ₂ CONH ₂ , -CH ₂ SCH ₃ , -CH ₂ SH, -CH ₂ (CH ₂ ) ₃ NH ₂ or -CH ₂ CH ₂ CH ₂ NHC (NH) NH ₂ . In yet another embodiment, n is 1 and R ² and R ¹⁶ together with the atoms to which they are attached form a pyrrolidine ring.

In yet another preferred embodiment of the compounds of formulas (I) - (IV), R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cyclobutyl or substituted cyclobutyl ring. Preferably, the substituted cyclobutyl ring is substituted with one or more substituents selected from alkanyl, substituted alkanyl, halogen, hydroxy, carboxyl and alkoxycarbonyl.

ausgewählt.In yet another preferred embodiment of the compounds of formulas (I) - (IV), R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cyclopentyl or substituted cyclopentyl ring. Preferably, the cyclopentyl ring is substituted with alkanyl, substituted alkanyl, halogen, hydroxy, carboxyl or alkoxycarbonyl. More preferably, the cyclopentyl ring is substituted with alkanyl. Even more preferred is the cyclopentyl ring

selected.

In a more specific version of the above embodiments, R ^{7 is} preferably hydrogen.

ausgewählt.In yet another preferred embodiment of the compounds of formulas (I) - (IV), R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cyclohexyl or substituted cyclohexyl ring. Preferably, the cyclohexyl ring is substituted with alkanyl, substituted alkanyl, halogen, hydroxy, carboxyl or alkoxycarbonyl. More preferably, the cyclohexyl ring is substituted with alkanyl. Even more preferred is the cyclohexyl ring

selected.

In a more specific version of the above embodiments, R ^{7 is} preferably hydrogen.

In yet another preferred embodiment of the compounds of formulas (I) - (IV), R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring.

ausgewählt,
wobei
Z O, S(O)_p oder NR¹⁸ ist;
p 0, 1 oder 2 ist und
R¹⁸ aus Wasserstoff, Alkyl, substituiertem Alkyl, Acyl und Alkoxycarbonyl ausgewählt ist.In one embodiment, n is 0. In another embodiment, n is 1 and R ² is hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, t-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4- Bromobenzyl, 2-imidazolyl, 2-indolyl, -CH ₂ OH, -CH (OH) CH ₃ , -CH ₂ CO ₂ H, -CH ₂ CH ₂ CO ₂ H, -CH ₂ CONH ₂ , -CH ₂ CH ₂ CONH ₂ , -CH ₂ CH ₂ SCH ₃ , -CH ₂ SH, -CH ₂ (CH ₂ ) ₃ NH ₂ or -CH ₂ CH ₂ CH ₂ NHC (NH) NH ₂ . In yet another embodiment, n is 1 and R ² and R ¹⁶ together with the atoms to which they are attached form one Pyrrolidine. Preferably, R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cycloheteroalkanyl ring. More preferred is the cycloheteroalkanyl ring

selected,
in which
Z is O, S (O) _p or NR ¹⁸ ;
p is 0, 1 or 2 and
R ¹⁸ is selected from hydrogen, alkyl, substituted alkyl, acyl and alkoxycarbonyl.

ausgewählt.More preferred is the cycloheteroalkanyl ring

selected.

In a more specific version of the above embodiments, R ^{7 is} preferably hydrogen.

In yet another embodiment of the compounds of formulas (I) - (IV), R ⁴ and R ⁵ together with the carbon atom to which they are attached form a bridged cycloalkyl ring. In one embodiment, n is 0. In another embodiment, n is 1 and R ² is hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, t-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4- Bromobenzyl, 2-imidazolyl, 2-indolyl, -CH ₂ OH, -CH (OH) CH ₃ , -CH ₂ CO ₂ H, -CH ₂ CH ₂ CO ₂ H, -CH ₂ CONH ₂ , -CH ₂ CH ₂ CONH ₂ , -CH ₂ CH ₂ SCH ₃ , -CH ₂ SH, -CH ₂ (CH ₂ ) ₃ NH ₂ or -CH ₂ CH ₂ CH ₂ NHC (NH) NH ₂ . In another embodiment, n is 1 and R ² and R ¹⁶ together with the atoms to which they are attached form a pyrrolidine ring. Preferably, the bridged cycloalkyl radical

In a more specific version of the above embodiments, R ^{7 is} preferably hydrogen.

In yet another embodiment of the compounds of formulas (I) - (IV) Y is O, R ⁶ and R ^{7 are} hydrogen, R ^{4 is} alkyl or cycloalkyl, R ^{5 is} hydrogen or alkyl and R ^{3 is} hydrogen or alkyl. In one embodiment, n is 0. In another embodiment, n is 1 and R ² is hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, t-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4- Bromobenzyl, 2-imidazolyl, 2-indolyl, -CH ₂ OH, -CH (OH) CH ₃ , -CH ₂ CO ₂ H, -CH ₂ CH ₂ CO ₂ H, -CH ₂ CONH ₂ , -CH ₂ CH ₂ CONH ₂ , -CH ₂ CH ₂ SCH ₃ , -CH ₂ SH, -CH ₂ (CH ₂ ) ₃ NH ₂ or -CH ₂ CH ₂ CH ₂ NHC (NH) NH ₂ . In yet another embodiment, n is 1 and R ² and R ¹⁶ together with the atoms to which they are attached form a pyrrolidine ring. Preferably when R ^{4 is} cycloalkyl, R ^{5 is} hydrogen or methyl and R ^{3 is} hydrogen or methyl. Preferably, R ^{3 is} hydrogen, R ^{4 is} isobutyl and R ^{5 is} hydrogen.

ist A NR¹⁹, O oder S;
ist B Alkyl, substituiertes Alkyl, Alkoxy, Halogen, Hydroxy, Carboxyl, Alkoxycarbonyl oder Amino;
ist R¹⁹ Wasserstoff, Alkyl, Cycloalkyl oder Aryl;
ist j eine ganze Zahl von 0 bis 4;
ist k eine ganze Zahl von 1 bis 4 und
ist l eine ganze Zahl von 0 bis 3.
Stärker bevorzugt ist k 1.In yet another embodiment of the compounds of formulas (I) - (IV) Y is O, R ⁵ and R ^{7 are} hydrogen or alkanyl, R ³ and R ^{6 are} hydrogen and R ^{4 is} substituted heteroalkyl. Preferably, R ^{4 is}

A is NR ¹⁹ , O or S;
B is alkyl, substituted alkyl, alkoxy, halogen, hydroxy, carboxyl, alkoxycarbonyl or amino;
R ^{19 is} hydrogen, alkyl, cycloalkyl or aryl;
j is an integer from 0 to 4;
k is an integer from 1 to 4 and
l is an integer from 0 to 3.
More preferably, k is 1.

ist h eine ganze Zahl von 1 bis 6 und
ist i eine ganze Zahl von 0 bis 6.In yet another embodiment of the compounds of formulas (I) - (IV) Y is O, R ⁵ and R ^{7 are} hydrogen or alkanyl, R ³ and R ^{6 are} hydrogen and R ^{4 is} substituted alkanyl, cycloalkanyl or substituted cycloalkanyl. Preferably, R ^{4 is} selected from. Preferably, R ^{4 is}

h is an integer from 1 to 6 and
i is an integer from 0 to 6.

ausgewählt.More preferably h is 1, 2, 3 or 4 and i is 0 or 1. Even more preferably, R ^{4 is} off

selected.

wobei das GABA-Analogon der Formel (XIII) aus:
1-Aminomethyl-1-cyclohexanessigsäure;
1-Aminomethyl-1-(3-methylcyclohexan)essigsäure;
1-Aminomethyl-1-(4-methylcyclohexan)essigsäure;
1-Aminomethyl-1-(4-isopropylcyclohexan)essigsäure;
1-Aminomethyl-1-(4-tert.-butylcyclohexan)essigsäure;
1-Aminomethyl-1-(3,3-dimethylcyclohexan)essigsäure;
1-Aminomethyl-1-(3,3,5,5-tetramethylcyclohexan)essigsäure;
1-Aminomethyl-1-cyclopentanessigsäure;
1-Aminomethyl-1-(3-methylcyclopentan)essigsäure;
1-Aminomethyl-1-(3,4-dimethylcyclopentan)essigsäure;
7-Aminomethylbicyclo[2.2.1]hept-7-ylessigsäure;
9-Aminomethylbicyclo[3.3.1]non-9-ylessigsäure;
4-Aminomethyl-4-(tetrahydropyran-4-yl)essigsäure;
3-Aminomethyl-3-(tetrahydropyran-3-yl)essigsäure;
4-Aminomethyl-4-(tetrahydrothiopyran-4-yl)essigsäure;
3-Aminomethyl-3-(tetrahydrothiopyran-3-yl)essigsäure;
3-Aminomethyl-5-methylhexansäure;
3-Aminomethyl-5-methylheptansäure;
3-Aminomethyl-5-methyloctansäure;
3-Aminomethyl-5-methylnonansäure;
3-Aminomethyl-5-methyldecansäure;
3-Aminomethyl-5-cyclopropylhexansäure;
3-Aminomethyl-5-cyclobutylhexansäure;
3-Aminomethyl-5-cyclopentylhexansäure;
3-Aminomethyl-5-cyclohexylhexansäure;
3-Aminomethyl-5-phenylhexansäure;
3-Aminomethyl-5-phenylpentansäure;
3-Aminomethyl-4-cyclobutylbuttersäure;
3-Aminomethyl-4-cyclopentylbuttersäure;
3-Aminomethyl-4-cyclohexylbuttersäure;
3-Aminomethyl-4-phenoxybuttersäure;
3-Aminomethyl-5-phenoxyhexansäure und
3-Aminomethyl-5-benzylsulfanylpentansäure
ausgewählt ist.Preferably, compounds of formulas (I) - (IV) are derived from a GABA analog of formula (XIII):

wherein the GABA analog of formula (XIII) is selected from:
1-aminomethyl-1-cyclohexaneacetic acid;
1-Aminomethyl-1- (3-methylcyclohexane) acetic acid;
1-Aminomethyl-1- (4-methylcyclohexane) acetic acid;
1-Aminomethyl-1-acetic acid (4-isopropylcyclohexane);
1-Aminomethyl-1- (4-tert-butylcyclohexane) acetic acid;
1-Aminomethyl-1-acetic acid (3,3-dimethylcyclohexane);
1-Aminomethyl-1- (3,3,5,5-tetramethylcyclohexane) acetic acid;
1-Aminomethyl-1-cyclopentane acetic acid;
1-Aminomethyl-1- (3-methylcyclopentane) acetic acid;
1-Aminomethyl-1- (3,4-dimethylcyclopentane) acetic acid;
7-Aminomethyl-bicyclo [2.2.1] hept-7-yl acetic acid;
9-Aminomethyl-bicyclo [3.3.1] non-9-yl acetic acid;
4-Aminomethyl-4- (tetrahydropyran-4-yl) acetic acid;
3-Aminomethyl-3- (tetrahydropyran-3-yl) acetic acid;
4-Aminomethyl-4- (tetrahydrothiopyran-4-yl) acetic acid;
3-Aminomethyl-3- (tetrahydrothiopyran-3-yl) acetic acid;
3-aminomethyl-5-methylhexanoic acid;
3-Aminomethyl-5-methylheptanoic acid;
3-Aminomethyl-5-methyloctanoic acid;
3-Aminomethyl-5-methylnonanoic acid;
3-Aminomethyl-5-methyldecanoic acid;
3-Aminomethyl-5-cyclopropylhexansäure;
3-Aminomethyl-5-cyclobutylhexansäure;
3-Aminomethyl-5-cyclopentylhexansäure;
3-Aminomethyl-5-cyclohexylhexanoic acid;
3-Aminomethyl-5-phenylhexanoic acid;
3-Aminomethyl-5-phenyl-pentanoic acid;
3-Aminomethyl-4-cyclobutylbuttersäure;
3-Aminomethyl-4-cyclopentylbuttersäure;
3-Aminomethyl-4-cyclohexylbutyric acid;
3-Aminomethyl-4-phenoxybutyric acid;
3-aminomethyl-5-phenoxyhexanoic acid and
3-Aminomethyl-5-benzylsulfanylpentansäure
is selected.

wo R¹, R², R⁷ und R¹⁶ wie vorstehend definiert sind.Particularly preferred embodiments of the formula (I) include compounds of the formulas (V) and (VI):

where R ¹ , R ² , R ⁷ and R ^{16 are} as defined above.

In one embodiment of the compounds of the formulas (V) and (VI) n is 0. In another embodiment, n is 1 and R ² is hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, t-butyl, cyclopentyl, cyclohexyl , Phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 2-indolyl, -CH ₂ OH, -CH (OH) CH ₃ , -CH ₂ CO ₂ H, -CH ₂ CH ₂ CO ₂ H, -CH ₂ CONH ₂ , -CH ₂ CH ₂ CONH ₂ , -CH ₂ CH ₂ SCH ₃ , -CH ₂ SH, -CH ₂ (CH ₂ ) ₃ NH ₂ or -CH ₂ CH ₂ CH ₂ NHC (NH) NH ₂ . In the above embodiments, R ^{7 is} preferably hydrogen.

wo V O oder CH₂ ist.In another embodiment of the compounds of the formulas (V) and (VI) n is 1, R ^{1 is} R ²⁴ C (O) - or R ^{24 is} C (S) - and R ²⁴ is alkyl, substituted alkyl, heteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl. Preferably, R ^{24 is} methyl, ethyl, 2-propyl, t-butyl, -CH ₂ OCH (CH ₃ ) ₂ , phenyl or 3-pyridyl. In this embodiment, R ^{7 is} preferably hydrogen, alkanyl, substituted alkanyl, alkenyl, substituted alkenyl, aryl or substituted aryl. More preferably, R ^{7 is} hydrogen, methyl, ethyl, benzyl, -C (CH ₃ ) = CH ₂ , -CH ₂ C (O) N (CH ₃ ) ₂ ,

where V is O or CH ₂ .

Most preferably, R ^{7 is} hydrogen.

wo V O oder CH₂ ist.In yet another embodiment of the compounds of formulas (V) and (VI) n is 1, R ^{1 is} R ²⁵ OC (O) - or R ^{15 is} SC (O) - and R ²⁵ is alkyl, substituted alkyl, heteroalkyl, aryl , substituted aryl, heteroaryl or substituted heteroaryl. Preferably R ^{25 is} ethyl, 2-propyl, neo-pentyl, -CH ₂ OCH (CH ₃ ) ₂ , phenyl or 2-pyridyl. In this embodiment, R ^{7 is} preferably hydrogen, alkanyl, substituted alkanyl, alkenyl, substituted alkenyl, aryl or substituted aryl. More preferably R ^{7 is} hydrogen, methyl, ethyl, benzyl, C (CH ₃ ) = CH ₂ , -CH ₂ C (O) N (CH ₃ ) ₂ ,

where V is O or CH ₂ .

Most preferably, R ^{7 is} hydrogen.

und R¹⁵ ist aus Alkyl, substituiertem Alkyl, Cycloalkyl, substituiertem Cycloalkyl, Aryl, substituiertem Aryl, Heteroaryl und substituiertem Heteroaryl ausgewählt. Vorzugsweise ist R¹⁵ Methyl, Ethyl, Propyl, Isopropyl, Cyclopentyl, Cyclohexyl, Phenyl, 4-Hydroxyphenyl, Benzyl, 4-Hydroxybenzyl oder 3-Pyridyl. In einer spezielleren Version dieser Ausführungsform ist R⁷ Wasserstoff, Alkanyl, substituiertes Alkanyl, Alkenyl, substituiertes Alkenyl, Aryl oder substituiertes Aryl. Stärker bevorzugt ist R⁷ Wasserstoff, Methyl, Ethyl, Benzyl, -C(CH₃)=CH₂, -CH₂C(O)N(CH₃)₂,

wo V O oder CH₂ ist.In still another embodiment of the compounds of formulas (V) and (VI) R ^{1 is}

and R ¹⁵ is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl. Preferably R ^{15 is} methyl, ethyl, propyl, isopropyl, cyclopentyl, cyclohexyl, phenyl, 4-hydroxyphenyl, benzyl, 4-hydroxybenzyl or 3-pyridyl. In a more specific In the version of this embodiment, R ^{7 is} hydrogen, alkanyl, substituted alkanyl, alkenyl, substituted alkenyl, aryl or substituted aryl. More preferably, R ^{7 is} hydrogen, methyl, ethyl, benzyl, -C (CH ₃ ) = CH ₂ , -CH ₂ C (O) N (CH ₃ ) ₂ ,

where V is O or CH ₂ .

Preferably, R ^{7 is} hydrogen.

Particularly preferred embodiments of the compounds of formulas (V) and (VI) are compounds consisting of:
1 - {[((5-methyl-2-oxo-1,3-dioxol-4-en-4-yl) methoxy) carbonyl] aminomethyl) -1-cyclohexanoacetic acid and
3 - {[((5-methyl-2-oxo-1,3-dioxol-4-en-4-yl) methoxy) carbonyl] aminomethyl} -5-methylhexanoic acid
are selected.

ist m 0 und sind R⁸, R¹¹ und R¹² wie vorstehend definiert. In einer Ausführungsform der Verbindungen der Formeln (V) und (VI) ist R¹¹ Acyl, Alkoxycarbonyl, Aryloxycarbonyl, Cycloalkoxycarbonyl, Carbamoyl oder substituiertes Carbamoyl, ist R⁸ Wasserstoff, Alkoxycarbonyl, Alkyl, Aryl, Arylalkyl oder Cyano und ist R¹² Wasserstoff, Alkoxycarbonyl, Alkyl, substituiertes Alkyl, Aryl oder Arylalkyl. In einer anderen Ausführungsform der Verbindungen der Formeln (V) und (VI) ist R¹¹ aus Acetyl, Propionyl, Butyryl, Isobutyryl, Pivaloyl, Cyclopentancarbonyl, Cyclohexancarbonyl, Benzoyl, Phenacetyl, Methoxycarbonyl, Ethoxycarbonyl, Propoxycarbonyl, Isopropoxycarbonyl, Butoxycarbonyl, Isobutoxycarbonyl, sek.-Butoxycarbonyl, tert.-Butoxycarbonyl, Cyclopentyloxycarbonyl, Cyclohexyloxycarbonyl, Phenoxycarbonyl, Benzyloxycarbonyl, Carbamoyl, N-Methylcarbamoyl, N-Ethylcarbamoyl, N-Propylcarbamoyl, N-Isopropylcarbamoyl, N-Butylcarbamoyl, N-Isobutylcarbamoyl, N-sek.-Butylcarbamoyl, N-tert.-Butylcarbamoyl, N-Cyclopentylcarbamoyl, N-Cyclohexylcarbamoyl, N-Phenylcarbamoyl, N-Benzylcarbamoyl, N,N-Dimethylcarbamoyl, N,N-Diethylcarbamoyl, N,N-Dipropylcarbamoyl, N,N-Diisopropylcarbamoyl, N,N-Dibutylcarbamoyl, N,N-Dibenzylcarbamoyl, N-Pyrrolidinylcarbamoyl, N-Piperidinylcarbamoyl und N-Morpholinylcarbamoyl ausgewählt. In noch einer anderen Ausführungsform der Verbindungen der Formeln (V) und (VI) ist R¹¹ aus Acetyl, Propionyl, Butyryl, Isobutyryl, Cyclohexancarbonyl, Benzoyl, Phenacetyl, Methoxycarbonyl, Ethoxycarbonyl, Propoxycarbonyl, Isopropoxycarbonyl, Butoxycarbonyl, Cyclohexyloxycarbonyl, Phenoxycarbonyl, Benzyloxycarbonyl, Carbamoyl, N-Methylcarbamoyl, N-Ethylcarbamoyl, N-Propylcarbamoyl, N-Isopropylcarbamoyl, N-Phenylcarbamoyl, N-Benzylcarbamoyl, N,N-Dimethylcarbamoyl, N,N-Diethylcarbamoyl, N,N-Dipropylcarbamoyl, N-Pyrrolidinylcarbamoyl, N-Piperidinylcarbamoyl und N-Morpholinylcarbamoyl.In still another embodiment of the compounds of formulas (V) and (VI) R ^{1 is}

m is 0 and R ⁸ , R ¹¹ and R ^{12 are} as defined above. In one embodiment of the compounds of the formulas (V) and (VI) R ^{11 is} acyl, alkoxycarbonyl, aryloxycarbonyl, cycloalkoxycarbonyl, carbamoyl or substituted carbamoyl, R ^{8 is} hydrogen, alkoxycarbonyl, alkyl, aryl, arylalkyl or cyano and R ^{12 is} hydrogen, Alkoxycarbonyl, alkyl, substituted alkyl, aryl or arylalkyl. In another embodiment of the compounds of formulas (V) and (VI), R ^{11 is} acetyl, propionyl, butyryl, isobutyryl, pivaloyl, cyclopentanecarbonyl, cyclohexanecarbonyl, benzoyl, phenacetyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec Tert-butoxycarbonyl, tert-butoxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-isobutylcarbamoyl, N-sec-butylcarbamoyl, N-tert-butylcarbamoyl, N-cyclopentylcarbamoyl, N -cyclohexylcarbamoyl, N-phenylcarbamoyl, N -benzylcarbamoyl, N, N -dimethylcarbamoyl, N, N -diethylcarbamoyl, N, N -dipropylcarbamoyl, N, N -diisopropylcarbamoyl, N, N Dibutylcarbamoyl, N, N-dibenzylcarbamoyl, N-pyrrolidinylcarbamoyl, N-piperidinylcarbamoyl and N-morpholinylcarbamoyl. In still another embodiment of the compounds of formulas (V) and (VI) R ^{11 is} acetyl, propionyl, butyryl, isobutyryl, cyclohexanecarbonyl, benzoyl, phenacetyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, cyclohexyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, Carbamoyl, N-methylcarbamoyl, N -ethylcarbamoyl, N -propylcarbamoyl, N-isopropylcarbamoyl, N-phenylcarbamoyl, N -benzylcarbamoyl, N, N -dimethylcarbamoyl, N, N -diethylcarbamoyl, N, N -dipropylcarbamoyl, N -pyrrolidinylcarbamoyl, N- Piperidinylcarbamoyl and N-morpholinylcarbamoyl.

In one embodiment of the compounds of formulas (V) and (VI), R ^{8 is selected} from hydrogen, methyl, ethyl, propyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl and cyano. Preferably, R ^{8 is selected} from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl.

In yet another embodiment of the compounds of formulas (V) and (VI) R ^{12 is selected} from hydrogen, methyl, ethyl, propyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, phenoxycarbonyl and benzyloxycarbonyl. Preferably, R ^{12 is selected} from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl.

In yet another embodiment of the compounds of formulas (V) and (VI), R ^{11 is selected} from hydrogen, alkoxycarbonyl, alkyl, substituted alkyl, aryl, and arylalkyl and form R ⁸ and R ¹² together with the carbon atoms to which they are attached, a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring. Preferably, R ^{11 is selected} from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl, and R ⁸ and R ¹² together with the carbon atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl - or substituted. Cycloheteroalkyl. More preferably R ^{11 is} hydrogen or methyl and R ⁸ and R ¹² , taken together with the carbon atoms to which they are attached, form a 2-cyclopenten-1-one, 2-cyclohexen-1-one, 2- (5H) Furanone or 5,6-dihydropyran-2-one ring.

In yet another embodiment of the compounds of formulas (V) and (VI), R ^{32 is selected} from hydrogen, alkoxycarbonyl, alkyl, substituted alkyl, aryl, and arylalkyl, and R ⁸ and R ¹¹ form together with the carbon atoms to which they are attached , a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring. Preferably, R ^{12 is selected} from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl, and R ⁸ and R ¹¹ together with the carbon atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl - or substituted Cycloheteroalkylring. More preferably R ^{1 2 is selected} from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl, and R ⁸ and R ¹¹ together with the carbon atoms to which they are attached form a γ-butyrolactone, δ Valerolactone or 2,2-dimethyl-1,3-dioxane-4,6-dione ring.

wo V O oder CH₂ ist.In a more specific version of the above embodiments of the compounds of formulas (V) and (VI), R ^{7 is} hydrogen, alkanyl, substituted alkanyl, alkenyl, substituted alkenyl, aryl or substituted aryl. More preferably, R ^{7 is} hydrogen, methyl, ethyl, benzyl, -C (CH ₃ ) = CH ₂ , -CH ₂ C (O) N (CH ₃ ) ₂ ,

where V is O or CH ₂ .

Most preferably, R ^{7 is} hydrogen.

Particularly preferred embodiments of the compounds of formulas (V) and (VI) are compounds consisting of:
Piperidinium-1 - {(1-methyl-3-oxobut-1-enyl) aminomethyl) -1-cyclohexanacetat;
Piperidinium-1- {1 - [(2-oxotetrahydrofuran-3-ylidene) ethyl] aminomethyl) -1-cyclohexanacetat;
Piperidinium-1 - {(2-carbomethoxycyclopent-1-enyl) aminomethyl} -1-cyclohexanacetat;
and
Piperidinium-1 - {(1-methyl-2- (ethoxycarbonyl) -3-ethoxy-3-oxoprop-1-enyl) aminomethyl) -1-cyclohexanacetat
are selected.

oder eines pharmazeutisch verträglichen Salzes, Hydrats oder Solvats davon auf, wobei:
n, R², R⁷, R¹³, R¹⁴, R¹⁶ und R²⁵ wie vorstehend definiert sind.In a particularly preferred embodiment, compounds of the formula (IV) have the structure of the formulas (VII) or (VIII):

or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
n, R ² , R ⁷ , R ¹³ , R ¹⁴ , R ¹⁶ and R ^{25 are} as defined above.

In a preferred embodiment, the compounds of formulas (VII) and (VIII) do not include the following compounds:
if either R ¹³ or R ^{14 is} hydrogen, alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl, cycloalkoxycarbonyl or substituted cycloalkoxycarbonyl, then the other radical of R ¹³ and R ^{14 is} not hydrogen and
R ²⁵ C (O) is not a unit derived from a bile acid.

In one embodiment of the compounds of formulas (VII) and (VIII), n is 0. In another embodiment, n is 1. When n is 1, the α-amino acid preferably has the stereochemical L-configuration.

wo V O oder CH₂ ist.In another embodiment of the compounds of formulas (VII) and (VIII) R ^{7 is} hydrogen, alkanyl, substituted alkanyl, alkenyl, substituted alkenyl, aryl or substituted aryl. Preferably, R ^{7 is} hydrogen, methyl, ethyl, benzyl, -C (CH ₃ ) = CH ₂ , -CH ₂ C (O) N (CH ₃ ) ₂ ,

where V is O or CH ₂ .

Most preferably, R ^{7 is} hydrogen.

In yet another embodiment of the compounds of formulas (VII) and (VIII) n is 0. In yet another embodiment of the compounds of formulas (VII) and (VIII), n is 1, R ^{16 is} hydrogen and R ² is hydrogen, Methyl, 2-propyl, 2-butyl, isobutyl, tert -butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 2-indolyl, -CH ₂ OH, -CH (OH ) CH ₃ , -CH ₂ CO ₂ H, -CH ₂ CH ₂ CO ₂ H, -CH ₂ CONH ₂ , -CH ₂ CH ₂ CONH ₂ , -CH ₂ CH ₂ SCH ₃ , -CH ₂ SH, -CH ₂ (CH ₂ ) ₃ NH ₂ or -CH ₂ CH ₂ CH ₂ NHC (NH) NH ₂ . Preferably, R ^{16 is} hydrogen and R ² is hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, tert-butyl, cyclohexyl, phenyl or benzyl. In yet another embodiment, n is 1 and R ² and R ¹⁶ together with the atoms to which they are attached form a pyrrolidine ring.

In yet another embodiment of the compounds of formulas (VII) and (VIII) R ^{25 is} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1, 1-Dimethoxyethyl, 1,1-diethoxyethyl, 1- (1,3-dioxolan-2-yl) ethyl, 1- (1,3-dioxan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1- Diethoxypropyl, 1- (1,3-dioxolan-2-yl) propyl, 1- (1,3-dioxan-2-yl) propyl, 1,1-dimethoxybutyl, 1,1- Diethoxybutyl, 1- (1,3-dioxolan-2-yl) butyl, 1- (1,3-dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3 Dioxolan-2-yl) benzyl, 1- (1,3-dioxan-2-yl) benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3 Dioxolan-2-yl) -2-phenethyl, 1- (1,3-dioxan-2-yl) -2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, Styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R ^{13 is} methyl and R ^{14 is} hydrogen.

In yet another embodiment of the compounds of formulas (VII) and (VIII) R ^{25 is} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1, 1-Dimethoxyethyl, 1,1-diethoxyethyl, 1- (1,3-dioxolan-2-yl) ethyl, 1- (1,3-dioxan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1- Diethoxypropyl, 1- (1,3-dioxolan-2-yl) propyl, 1- (1,3-dioxan-2-yl) propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1- (1,3 Dioxolan-2-yl) butyl, 1- (1,3-dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3-dioxolan-2-yl) benzyl , 1- (1,3-dioxan-2-yl) benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3-dioxolan-2-yl) - 2-phenethyl, 1- (1,3-dioxan-2-yl) -2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl and 3-pyridyl, R ^{13 is} ethyl and R ^{14 is} hydrogen.

In yet another embodiment of the compounds of formulas (VII) and (VIII) R ^{25 is} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1, 1-Dimethoxyethyl, 1,1-diethoxyethyl, 1- (1,3-dioxolan-2-yl) ethyl, 1- (1,3-dioxan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1- Diethoxypropyl, 1- (1,3-dioxolan-2-yl) propyl, 1- (1,3-dioxan-2-yl) propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1- (1,3 Dioxolan-2-yl) butyl, 1- (1,3-dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3-dioxolan-2-yl) benzyl , 1- (1,3-dioxan-2-yl) benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3-dioxolan-2-yl) - 2-phenethyl, 1- (1,3-dioxan-2-yl) -2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl and 3-pyridyl, R ^{13 is} propyl and R ^{14 is} hydrogen.

In yet another embodiment of the compounds of formulas (VII) and (VIII) R ^{25 is} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1, 1-Dimethoxyethyl, 1,1-diethoxyethyl, 1- (1,3-dioxolan-2-yl) ethyl, 1- (1,3-dioxan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1- Diethoxypropyl, 1- (1,3-dioxolan-2-yl) propyl, 1- (1,3-dioxan-2-yl) propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1- (1,3 Dioxolan-2-yl) butyl, 1- (1,3-dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3-dioxolan-2-yl) benzyl , 1- (1,3-dioxan-2-yl) benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3-dioxolan-2-yl) - 2-phenethyl, 1- (1,3-dioxan-2-yl) -2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl and 3-pyridyl, R ^{13 is} isopropyl and R ^{14 is} hydrogen.

In yet another embodiment of the compounds of formulas (VII) and (VIII) R ^{25 is} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1, 1-Dimethoxyethyl, 1,1-diethoxyethyl, 1- (1,3-dioxolan-2-yl) ethyl, 1- (1,3-dioxan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1- Diethoxypropyl, 1- (1,3-dioxolan-2-yl) propyl, 1- (1,3-dioxan-2-yl) propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1- (1,3 Dioxolan-2-yl) butyl, 1- (1,3-dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3-dioxolan-2-yl) benzyl , 1- (1,3-dioxan-2-yl) benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3-dioxolan-2-yl) - 2-phenethyl, 1- (1,3-dioxan-2-yl) -2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl and 3-pyridyl, R ^{13 is} butyl and R ^{14 is} hydrogen.

In yet another embodiment of the compounds of formulas (VII) and (VIII) R ^{25 is} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1, 1-Dimethoxyethyl, 1,1-diethoxyethyl, 1- (1,3-dioxolan-2-yl) ethyl, 1- (1,3-dioxan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1- Diethoxypropyl, 1- (1,3-dioxolan-2-yl) propyl, 1- (1,3-dioxan-2-yl) propyl, 1,1-dimethoxybutyl, 1,1- Diethoxybutyl, 1- (1,3-dioxolan-2-yl) butyl, 1- (1,3-dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3 Dioxolan-2-yl) benzyl, 1- (1,3-dioxan-2-yl) benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3 Dioxolan-2-yl) -2-phenethyl, 1- (1,3-dioxan-2-yl) -2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, When styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl are selected, R ^{13 is} isobutyl and R ^{14 is} hydrogen.

In yet another embodiment of the compounds of formulas (VII) and (VIII) R ^{25 is} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1, 1-Dimethoxyethyl, 1,1-diethoxyethyl, 1- (1,3-dioxolan-2-yl) ethyl, 1- (1,3-dioxan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1- Diethoxypropyl, 1- (1,3-dioxolan-2-yl) propyl, 1- (1,3-dioxan-2-yl) propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1- (1,3 Dioxolan-2-yl) butyl, 1- (1,3-dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3-dioxolan-2-yl) benzyl , 1- (1,3-dioxan-2-yl) benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3-dioxolan-2-yl) - 2-phenethyl, 1- (1,3-dioxan-2-yl) -2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl and 3-pyridyl, R ^{13 is} sec-butyl and R ^{14 is} hydrogen.

In yet another embodiment of the compounds of formulas (VII) and (VIII) R ^{25 is} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1, 1-Dimethoxyethyl, 1,1-diethoxyethyl, 1- (1,3-dioxolan-2-yl) ethyl, 1- (1,3-dioxan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1- Diethoxypropyl, 1- (1,3-dioxolan-2-yl) propyl, 1- (1,3-dioxan-2-yl) propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1- (1,3 Dioxolan-2-yl) butyl, 1- (1,3-dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3-dioxolan-2-yl) benzyl , 1- (1,3-dioxan-2-yl) benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3-dioxolan-2-yl) - 2-phenethyl, 1- (1,3-dioxan-2-yl) -2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl and 3-pyridyl, R ^{13 is} tert-butyl and R ^{14 is} hydrogen.

In yet another embodiment of the compounds of formulas (VII) and (VIII) R ^{25 is} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1, 1-Dimethoxyethyl, 1,1-diethoxyethyl, 1- (1,3-dioxolan-2-yl) ethyl, 1- (1,3-dioxan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1- Diethoxypropyl, 1- (1,3-dioxolan-2-yl) propyl, 1- (1,3-dioxan-2-yl) propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1- (1,3 Dioxolan-2-yl) butyl, 1- (1,3-dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3-dioxolan-2-yl) benzyl , 1- (1,3-dioxan-2-yl) benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3-dioxolan-2-yl) - 2-phenethyl, 1- (1,3-dioxan-2-yl) -2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl and 3-pyridyl, R ^{13 is} cyclopentyl and R ^{14 is} hydrogen.

In yet another embodiment of the compounds of formulas (VII) and (VIII) R ^{25 is} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1, 1-Dimethoxyethyl, 1,1-diethoxyethyl, 1- (1,3-dioxolan-2-yl) ethyl, 1- (1,3-dioxan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1- Diethoxypropyl, 1- (1,3-dioxolan-2-yl) propyl, 1- (1,3-dioxan-2-yl) propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1- (1,3 Dioxolan-2-yl) butyl, 1- (1,3-dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3-dioxolan-2-yl) benzyl , 1- (1,3-dioxan-2-yl) benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3-dioxolan-2-yl) - 2-phenethyl, 1- (1,3-dioxan-2-yl) -2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl and 3-pyridyl, R ^{13 is} cyclohexyl and R ^{14 is} hydrogen.

In yet another embodiment of the compounds of formulas (VII) and (VIII) R ^{25 is} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1, 1-Dimethoxyethyl, 1,1-diethoxyethyl, 1- (1,3-dioxolan-2-yl) ethyl, 1- (1,3-dioxan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1- Diethoxypropyl, 1- (1,3-dioxolan-2-yl) propyl, 1- (1,3-dioxan-2-yl) propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1- (1,3 Dioxolan-2-yl) butyl, 1- (1,3-dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3-dioxolan-2-yl) benzyl , 1- (1,3-dioxan-2-yl) benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3-dioxolan-2-yl) - 2-phenethyl, 1- (1,3-dioxan-2-yl) -2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl and 3-pyridyl, R ^{13 is} methyl and R ^{14 is} methyl.

In yet another embodiment of the compounds of formulas (VII) and (VIII) R ^{25 is} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1, 1-Dimethoxyethyl, 1,1-diethoxyethyl, 1- (1,3-dioxolan-2-yl) ethyl, 1- (1,3-dioxan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1- Diethoxypropyl, 1- (1,3-dioxolan-2-yl) propyl, 1- (1,3-dioxan-2-yl) propyl, 1,1-dimethoxybutyl, 1,1- Diethoxybutyl, 1- (1,3-dioxolan-2-yl) butyl, 1- (1,3-dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3 Dioxolan-2-yl) benzyl, 1- (1,3-dioxan-2-yl) benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3 Dioxolan-2-yl) -2-phenethyl, 1- (1,3-dioxan-2-yl) -2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, Styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R ^{13 is} methoxycarbonyl and R ^{14 is} methyl.

In yet another embodiment of the compounds of formulas (VII) and (VIII) R ^{25 is} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1, 1-dimethoxyetyl, 1,1-diethoxyethyl, 1- (1,3-dioxolan-2-yl) ethyl, 1- (1,3-dioxan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1- Diethoxypropyl, 1- (1,3-dioxolan-2-yl) propyl, 1- (1,3-dioxan-2-yl) propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1- (1,3 Dioxolan-2-yl) butyl, 1- (1,3-dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3-dioxolan-2-yl) benzyl , 1- (1,3-dioxan-2-yl) benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3-dioxolan-2-yl) - 2-phenethyl, 1- (1,3-dioxan-2-yl) -2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl and 3-pyridyl, R ^{13 is} ethoxycarbonyl and R ^{14 is} methyl.

In yet another embodiment of the compounds of formulas (VII) and (VIII) R ^{25 is} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1, 1-dimethoxyetyl, 1,1-diethoxyethyl, 1- (1,3-dioxolan-2-yl) ethyl, 1- (1,3-dioxan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1- Diethoxypropyl, 1- (1,3-dioxolan-2-yl) propyl, 1- (1,3-dioxan-2-yl) propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1- (1,3 Dioxolan-2-yl) butyl, 1- (1,3-dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3-dioxolan-2-yl) benzyl , 1- (1,3-dioxan-2-yl) benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3-dioxolan-2-yl) - 2-phenethyl, 1- (1,3-dioxan-2-yl) -2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl and 3-pyridyl, R ^{13 is} propoxycarbonyl and R ^{14 is} methyl.

In yet another embodiment of the compounds of formulas (VII) and (VIII) R ^{25 is} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1, 1-dimethoxyetyl, 1,1-diethoxyethyl, 1- (1,3-dioxolan-2-yl) ethyl, 1- (1,3-dioxan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1- Diethoxypropyl, 1- (1,3-dioxolan-2-yl) propyl, 1- (1,3-dioxan-2-yl) propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1- (1,3 Dioxolan-2-yl) butyl, 1- (1,3-dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3-dioxolan-2-yl) benzyl , 1- (1,3-dioxan-2-yl) benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3-dioxolan-2-yl) - 2-phenethyl, 1- (1,3-dioxan-2-yl) -2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, When cyclohexyl and 3-pyridyl are selected, R ^{13 is} isopropoxycarbonyl and R ^{14 is} methyl.

In yet another embodiment of the compounds of formulas (VII) and (VIII) R ^{25 is} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1, 1-Dimethoxyethyl, 1,1-diethoxyethyl, 1- (1,3-dioxolan-2-yl) ethyl, 1- (1,3-dioxan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1- Diethoxypropyl, 1- (1,3-dioxolan-2-yl) propyl, 1- (1,3-dioxan-2-yl) propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1- (1,3 Dioxolan-2-yl) butyl, 1- (1,3-dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3-dioxolan-2-yl) benzyl , 1- (1,3-dioxan-2-yl) benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3-dioxolan-2-yl) - 2-phenethyl, 1- (1,3-dioxan-2-yl) -2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl and 3-pyridyl, R ^{13 is} butoxycarbonyl and R ^{14 is} methyl.

In yet another embodiment of the compounds of formulas (VII) and (VIII) R ^{25 is} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1, 1-Dimethoxyethyl, 1,1-diethoxyethyl, 1- (1,3-dioxolan-2-yl) ethyl, 1- (1,3-dioxan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1- Diethoxypropyl, 1- (1,3-dioxolan-2-yl) propyl, 1- (1,3-dioxan-2-yl) propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1- (1,3 Dioxolan-2-yl) butyl, 1- (1,3-dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3-dioxolan-2-yl) benzyl , 1- (1,3-dioxan-2-yl) benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3-dioxolan-2-yl) - 2-phenethyl, 1- (1,3-dioxan-2-yl) -2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl and 3-pyridyl, R ^{13 is} isobutoxycarbonyl and R ^{14 is} methyl.

In yet another embodiment of the compounds of formulas (VII) and (VIII) R ^{25 is} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1, 1-Dimethoxyethyl, 1,1-diethoxyethyl, 1- (1,3-dioxolan-2-yl) ethyl, 1- (1,3-dioxan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1- Diethoxypropyl, 1- (1,3-dioxolan-2-yl) propyl, 1- (1,3-dioxan-2-yl) propyl, 1,1-dimethoxybutyl, 1,1- Diethoxybutyl, 1- (1,3-dioxolan-2-yl) butyl, 1- (1,3-dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3 Dioxolan-2-yl) benzyl, 1- (1,3-dioxan-2-yl) benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3 Dioxolan-2-yl) -2-phenethyl, 1- (1,3-dioxan-2-yl) -2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, Styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R ^{13 is} sec-butoxycarbonyl and R ^{14 is} methyl.

In yet another embodiment of the compounds of formulas (VII) and (VIII) R ^{25 is} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1, 1-Dimethoxyethyl, 1,1-diethoxyethyl, 1- (1,3-dioxolan-2-yl) ethyl, 1- (1,3-dioxan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1- Diethoxypropyl, 1- (1,3-dioxolan-2-yl) propyl, 1- (1,3-dioxan-2-yl) propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1- (1,3 Dioxolan-2-yl) butyl, 1- (1,3-dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3-dioxolan-2-yl) benzyl , 1- (1,3-dioxan-2-yl) benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3-dioxolan-2-yl) - 2-phenethyl, 1- (1,3-dioxan-2-yl) -2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, When cyclohexyl and 3-pyridyl are selected, R ^{13 is} tert-butoxycarbonyl and R ^{14 is} methyl.

In yet another embodiment of the compounds of formulas (VII) and (VIII) R ^{25 is} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1, 1-Dimethoxyethyl, 1,1-diethoxyethyl, 1- (1,3-dioxolan-2-yl) ethyl, 1- (1,3-dioxan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1- Diethoxypropyl, 1- (1,3-dioxolan-2-yl) propyl, 1- (1,3-dioxan-2-yl) propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1- (1,3 Dioxolan-2-yl) butyl, 1- (1,3-dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3-dioxolan-2-yl) benzyl , 1- (1,3-dioxan-2-yl) benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3-dioxolan-2-yl) - 2-phenethyl, 1- (1,3-dioxan-2-yl) -2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl and 3-pyridyl, R ^{13 is} cyclohexylkoxycarbonyl and R ^{14 is} methyl.

In another embodiment of the compounds of the formulas (VII) and (VIII), R ^{25 is} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1, 1-dimethoxyetyl, 1,1-diethoxyethyl, 1- (1,3-dioxolan-2-yl) ethyl, 1- (1,3-dioxan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1- Diethoxypropyl, 1- (1,3-dioxolan-2-yl) propyl, 1- (1,3-dioxan-2-yl) propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1- (1,3 Dioxolan-2-yl) butyl, 1- (1,3-dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3-dioxolan-2-yl) benzyl , 1- (1,3-dioxan-2-yl) benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3-dioxolan-2-yl) - 2-phenethyl, 1- (1,3-dioxan-2-yl) -2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl and 3-pyridyl selected, R ^{13 is} phenyl and R ^{14 is} hydrogen.

In yet another embodiment of the compounds of formulas (VII) and (VIII) R ^{25 is} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1, 1-dimethoxyetyl, 1,1-diethoxyethyl, 1- (1,3-dioxolan-2-yl) ethyl, 1- (1,3-dioxan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1- Diethoxypropyl, 1- (1,3-dioxolan-2-yl) propyl, 1- (1,3-dioxan-2-yl) propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1- (1,3 Dioxolan-2-yl) butyl, 1- (1,3-dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3-dioxolan-2-yl) benzyl , 1- (1,3-dioxan-2-yl) benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3-dioxolan-2-yl) - 2-phenethyl, 1- (1,3-dioxan-2-yl) -2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl and 3-pyridyl, R ^{13 is} benzyl and R ^{14 is} hydrogen.

In yet another embodiment of the compounds of formulas (VII) and (VIII) R ^{25 is} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1, 1-dimethoxyetyl, 1,1-diethoxyethyl, 1- (1,3-dioxolan-2-yl) ethyl, 1- (1,3-dioxan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1- Diethoxypropyl, 1- (1,3-dioxolan-2-yl) propyl, 1- (1,3-dioxan-2-yl) propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1- (1,3 Dioxolan-2-yl) butyl, 1- (1,3-dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3-dioxolan-2-yl) benzyl , 1- (1,3-dioxan-2-yl) benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3-dioxolan-2-yl) - 2-phenethyl, 1- (1,3-dioxan-2-yl) -2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl and 3-pyridyl, R ^{13 is} phenethyl and R ^{14 is} hydrogen.

In yet another embodiment of the compounds of formulas (VII) and (VIII) R ^{25 is} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1, 1-Dimethoxyethyl, 1,1-diethoxyethyl, 1- (1,3-dioxolan-2-yl) ethyl, 1- (1,3-dioxan-2-yl) ethyl, 1,1-dimethoxypropyl, 1,1- Diethoxypropyl, 1- (1,3-dioxolan-2-yl) propyl, 1- (1,3-dioxan-2-yl) propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1- (1,3 Dioxolan-2-yl) butyl, 1- (1,3-dioxan-2-yl) butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3-dioxolan-2-yl) benzyl , 1- (1,3-dioxan-2-yl) benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1- (1,3-dioxolan-2-yl) - 2-phenethyl, 1- (1,3-dioxan-2-yl) -2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl and 3-pyridyl, R ^{13 is} 3-pyridyl and R ^{14 is} hydrogen.

Particularly preferred embodiments of the compounds of formulas (VII) and (VIII) include compounds consisting of:
1 - {[(α-Acetoxyethoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid;
1 - {[(α-Propanoyloxyethoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid;
1 - {[(α-Butanoyloxyethoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid;
1 - {[(α-Isobutanoyloxyethoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid;
1 - {[(α-Pivaloxyethoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid;
1 - {[(α-Benzoyloxyethoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid;
1 - {{(α-Acetoxybutoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid;
1 - {[(α-Butanoyloxybutoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid;
1 - {[(α-Isobutanoyloxybutoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid;
1 - {[(α-Benzoyloxybutoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid;
1 - {[(α-Acetoxyisobutoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid;
1 - ([(α-Propanoyloxyisobutoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid;
1 - ([(α-Butanoyloxyisobutoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid;
1 - ([(α-Isobutanoyloxyisobutoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid;
1 - {[(α-Pivaloxyisobutoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid;
1 - {[(α-2,2-Diethoxypropanoyloxyisobutoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid;
1 - {[(α-2- (1,3-dioxolan-2-yl) propanoyloxyisobutoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid;
1 - {[(α- (2-amino-2-methylpropanoyl) oxyisobutoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid;
1 - {[(α-Benzoyloxyisobutoxy) carbonyl] aminomethyl-1-cyclohexaneacetic acid;
1 - {[(α-Nicotinoyloxyisobutoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid;
1 - {[(α-Acetoxyisopropoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid;
1 - {[(α-Butanoyloxyisopropoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid;
1 - {[(α-Isobutanoyloxyisopropoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid;
1 - {[(α-Benzoyloxyisopropoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid;
1 - {[(α-Acetoxybenzyloxy) carbonyl] aminomethyl) -1-cyclohexaneacetic acid;
1 - {[(α-Benzoyloxybenzyloxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid;
1 - {[(1- (3-Methylbutanoyloxy) -2-phenylethoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid;
1 - {[(1-Benzoyloxy-2-phenylethoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid;
1 - {[N - [(α-Isobutanoyloxyethoxy) carbonyl] -4-bromphenylalaninyl] aminomethyl} -1-cyclohexaneacetic acid;
3 - {[(α-Isobutanoyloxyethoxy) carbonyl] aminomethyl} -5-methylhexanoic acid;
3 - {[(α-isobutanoyloxyisobutoxy) carbonyl] aminomethyl} -5-methylhexanoic acid and
3 - {[(α-Benzoyloxyisobutoxy) carbonyl] aminomethyl} -5-methylhexanoic acid
are selected.

In one embodiment, the compounds have the structure of the formula (II):

In one embodiment of the compounds of formula (II), when R ³ , R ⁵ and R ^{6 are} hydrogen, R ^{4 is} not phenyl or substituted phenyl. More preferably, R ^{4 is} not 4-chlorophenyl.

In a preferred embodiment, the compounds of the formula (II) have the structure of the formulas (IX) and (X):

In one embodiment of the compounds of the formulas (IX) and (X), t is 0. In another embodiment, t is 1 and R ² is hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, t-butyl, cyclopentyl, cyclohexyl , Phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 2-indolyl, -CH ₂ OH, -CH (OH) CH ₃ , -CH ₂ CO ₂ H, -CH ₂ CH ₂ CO ₂ H, -CH ₂ CONH ₂ , -CH ₂ CH ₂ CONH ₂ , -CH ₂ CH ₂ SCH ₃ , -CH ₂ SH, -CH ₂ (CH ₂ ) ₃ NH ₂ or -CH ₂ CH ₂ CH ₂ NHC (NH) NH ₂ .

wo V O oder CH₂ ist.In still another embodiment of the compounds of formulas (IX) or (X), R ²⁰ and R ^{21 are} independently selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl. Preferably, R ²⁰ and R ^{31 are} independently selected from alkyl, substituted aryl, and heteroaryl. In one embodiment, R ^{20 is} methyl and R ²¹ is methyl. In this last embodiment, R ^{7 is} preferably hydrogen, methyl, ethyl, benzyl, -C (CH ₃ ) = CH ₂ , -CH ₂ C (O) N (CH ₃ ) ₂ ,

where V is O or CH ₂ .

Most preferably, R ^{7 is} hydrogen.

wo V O oder CH₂ ist.In another embodiment of the compounds of formulas (IX) or (X), R ²⁰ and R ²¹ together with the carbon atom to which they are attached form a cycloalkyl or substituted cycloalkyl ring. In one embodiment, R ²⁰ and R ²¹ together with the carbon atom to which they are attached form a cyclohexyl ring. In this last embodiment, R ^{7 is} preferably hydrogen, methyl, ethyl, benzyl, -C (CH ₃ ) = CH ₂ , CH ₂ C (O) N (CH ₃ ) ₂ ,

where V is O or CH ₂ .

Most preferably, R ^{7 is} hydrogen.

In one embodiment, the compounds have the structure of the formula (III):

In one embodiment of the compounds of the formula (III) n is 1, R ^{1 is} hydrogen and R ² is arylalkyl. Preferably, R ^{2 is} benzyl. In another embodiment of the compounds of the formula (III) n is 0 and R ¹ is R ²⁵ OC (O) -. Preferably, R ^{25 is} alkyl or substituted alkyl. More preferably R ^{25 is} ethyl. In yet another embodiment of the compounds of formula (III), R ²² and R ^{23 are} hydrogen. In yet another embodiment, R ²² and R ^{23 are} alkyl or substituted alkyl. Preferably, R ²² and R ^{23 are} methyl.

In a preferred embodiment, the compounds of the formula (III) have the structure of the formula (XI):

In one embodiment of the compounds of formula (XI) n is 1, X is NH, Y is O, R ^{1 is} hydrogen, R ^{2 is} benzyl, R ^{22 is} methyl and R ^{23 is} methyl. In another embodiment, n is 0, Y is O, R ^{1 is} R ²⁵ OC (O) -, R ^{21 is} ethyl, R ^{22 is} hydrogen and R ^{23 is} hydrogen.

In another embodiment, the compounds of the formula (III) have the structure of the formula (XII):

In one embodiment of the compounds of formula (XII) n is 1, X is NH, Y is O, R ^{1 is} hydrogen, R ^{2 is} benzyl, R ^{22 is} methyl and R ^{23 is} methyl. In another embodiment n is 0, Y is O, R ^{1 is} R ²⁵ OC (O) -, R ^{25 is} ethyl, R ^{22 is} hydrogen and R ^{23 is} hydrogen.

• (i) eine maximale Konzentration von H-G im Plasma (C_m) von mindestens 120% der C_max von H-G im Plasma, die durch kolonisches Verabreichen einer äquimolaren Dosis von H-G erreicht wird; und
• (ii) einen AUC-Wert, der mindestens 120% des AUC-Werts ist, der durch kolonisches Verabreichen einer äquimolaren Dosis von H-G erreicht wird,

zu erzeugen.Also described herein is a GABA analog derivative, MG, for administration to a patient in need of therapy, where M is a pro-unit and G is derived from a GABA analog, HG (where H is hydrogen). The pro-unit M cleaved once from G and any metabolite thereof shows a carcinogen toxic dose (TD ₅₀ ) in rats greater than 0.2 mmol / kg / day. Further, the pro unit M is cleaved after rat colonization in vivo at a sufficient rate of G to:

• (i) a maximum concentration of HG in the plasma (C _m ) of at least 120% of the C _max of HG in the plasma achieved by colonizing an equimolar dose of HG colonically; and
• (ii) an AUC value that is at least 120% of the AUC value achieved by colonically administering an equimolar dose of HG,

to create.

oder eines pharmazeutisch verträglichen Salzes, Hydrats oder Solvats davon auf, wobei:
M eine Proeinheit ist;
Y O oder S ist;
R Wasserstoff ist oder R und R⁶ zusammen mit den Atomen, an die sie gebunden sind, einen Azetidin-, substituierten Azetidin-, Pyrrolidin- oder substituierten Pyrrolidinring bilden;
R³ und R⁶ unabhängig voneinander aus Wasserstoff, Alkyl, substituiertem Alkyl, Aryl, substituiertem Aryl, Arylalkyl, substituiertem Arylalkyl, Cycloalkyl, substituiertem Cycloalkyl, Cycloheteroalkyl, substituiertem Cycloheteroalkyl, Heteroaryl, substituiertem Heteroaryl, Heteroarylalkyl und substituiertem Heteroarylalkyl ausgewählt sind; R⁴ und R⁵ unabhängig voneinander aus Wasserstoff, Alkyl, substituiertem Alkyl, Acyl, substituiertem Acyl, Aryl, substituiertem Aryl, Arylalkyl, substituiertem Arylalkyl, Cycloalkyl, substituiertem Cycloalkyl, Cycloheteroalkyl, substituiertem Cycloheteroalkyl, Heteroaryl, substituiertem Heteroaryl, Heteroarylalkyl und substituiertem Heteroarylalkyl ausgewählt sind oder gegebenenfalls R⁴ und R⁵ zusammen mit dem Kohlenstoffatom, an das sie gebunden sind, einen Cycloalkyl-, substituierten Cycloalkyl-, Cycloheteroalkyl-, substituierten Cycloheteroalkyl- oder verbrückten Cycloalkylring bilden und
R⁷ aus Wasserstoff, Alkyl, substituiertem Alkyl, Aryl, substituiertem Aryl, Arylalkyl, substituiertem Arylalkyl, Cycloalkyl, substituiertem Cycloalkyl, Cycloheteroalkyl, substituiertem Cycloheteroalkyl, Heteroalkyl, substituiertem Heteroalkyl, Heteroaryl, substituiertem Heteroaryl, Heteroarylalkyl und substituiertem Heteroarylalkyl ausgewählt ist.Preferably, MG has the structure of formula (XIV):

or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
M is a per unit;
YO or S is;
R is hydrogen or R and R ⁶ together with the atoms to which they are attached form an azetidine, substituted azetidine, pyrrolidine or substituted pyrrolidine ring;
R ³ and R ^{6 are} independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl; R ⁴ and R ^{5 are} independently selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl or optionally R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl or bridged cycloalkyl ring, and
R ^{7 is selected} from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl.

wobei:
n, X, R¹ und R² wie vorstehend definiert sind.In a preferred embodiment, M has the structure of formula (XV):

in which:
n, X, R ¹ and R ^{2 are} as defined above.

wobei R Wasserstoff ist und R³, R⁴, R⁵ und R⁶ wie vorstehend definiert sind.In an embodiment, MG includes compounds wherein once H-cleaved HG is substantially free of any lactam having the structure of formula (XVI):

wherein R is hydrogen and R ³ , R ⁴ , R ⁵ and R ^{6 are} as defined above.

Preferably, the pro-unit M or any M metabolite formed after cleavage of GM forms neither formaldehyde nor pivalic acid. In one embodiment, the pro-unit M is cleaved from rat G in vivo at a sufficient rate to give a C _max of HG in the plasma of at least 200%, and most preferably at least 1000% of the C _max of HG after in vivo colon administration to rats in the plasma achieved by colonically administering an equimolar dose of HG. Preferably, the pro-unit M is cleaved after colon administration to rats in vivo at a sufficient rate of G to give an AUC of HG in the plasma of at least 200%, and most preferably at least 500% of the AUC of HG in the plasma by colonizing an equimolar dose of HG. In another embodiment, the pro-unit M is cleaved from HG following oral administration to dogs (e.g., using a mini-pump osmotic device) at a dose of about 60 μmol equivalents HG per kg at a sufficient rate in vivo; at 12 hours after dosing to produce a plasma concentration of HG of at least 200% of the plasma concentration of HG achieved from an equimolar HG dose following the same administration procedure.

4.3 Synthesis of the compounds

The compounds described herein can be obtained via the synthetic methods illustrated in Schemes 1-17. Those skilled in the art will understand that a preferred synthetic route to the compounds is from attachment of pro-moieties to GABA analogs. Numerous methods have been described in the art for the synthesis of GABA analogs (see, e.g., Satzinger et al. U.S. Patent No. 4,024,175 ; Silverman et al. U.S. Patent No. 5,563,175 ; Horwell et al. U.S. Patent No. 6,020,370 ; Silverman et al. U.S. Patent No. 6,028,214 ; Horwell et al. U.S. Patent No. 6,103,932 ; Silverman et al. U.S. Patent No. 6,117,906 ; Silverman, International Disclosure No. WO 92/09560 ; Silverman et al., International Disclosure No. WO 93/23383 ; Horwell et al., International Disclosure No. WO 97/29101 ; Horwell et al., International Disclosure No. WO 97/33858 ; Horwell et al., International Disclosure No. WO 97/33859 ; Bryans et al., International Disclosure No. WO 98/17627 ; Guglietta et al., International Disclosure No. WO 99/08671 ; Bryans et al., International Disclosure No. WO 99/21824 ; Bryans et al., International Disclosure No. WO 99/31057 ; Belliotti et al., International Disclosure No. WO 99/31074 ; Bryans et al., International Disclosure No. WO 99/31075 ; Bryans et al., International Disclosure No. WO 99/61424 ; Bryans et al., International Disclosure No. WO 00/15611 ; Bryans, International Disclosure No. WO 00/31020 and Bryans et al., International Disclosure No. WO 00/50027 ). Other methods of synthesizing GABA analogs are known in the art which are readily available to one skilled in the art. The pro-units described herein are known in the art and may be prepared by known methods and attached to GABA analogs (See, e.g., Greene et al., Protective Groups in Organic Chemistry, (Wiley, 2nd ed., 1991). Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8 (John Wiley and Sons, 1971-1996); Beilstein Handbook of Organic Chemistry, Beilstein Institute of Organic Chemistry, Frankfurt, Germany, Fieser et Vol. 1-17, Wiley Interscience, Trost et al., "Comprehensive Organic Synthesis", Pergamon Press, 1991; "Theilheimer's Synthetic Methods of Organic Chemistry", Vols. 1-45, Karger, et al., "Reagents for Organic Synthesis". 1991; March, "Advanced Organs Chemistry," Wiley Interscience, 1991; Larock's "Comprehensive Organic Transformations," VCH Publishers, 1989; Paquette, "Encyclopedia of Reagents for Organ Synthesis," John Wiley & Sons, 1995; Bodanzsky, "Principles of Peptide Synthes Is ", Springer Verlag, 1984; Bodanzsky," Practice of Peptide Synthesis ", Springer Verlag, 1984).

Thus, starting materials useful for preparing compounds and intermediates thereof are commercially available or can be prepared by well-known synthetic methods. Other methods of synthesizing the prodrugs described herein are either described in the art or will be readily apparent to those skilled in the art in light of the references provided above and may be used to synthesize the compounds. Thus, the methods set forth in the Schemes are illustrative rather than comprehensive.

In any of the following schemes, after the amino group of a GABA analog has been functionalized with a pro-moiety or other protecting group, the carboxylic acid group can be converted to an ester or thioester by many synthetic methods well known to those skilled in the art. In a preferred embodiment, GABA analogs can be reacted with an alcohol or thiol in the presence of a coupling reagent (e.g., carbodiimide and dimethylaminopyridine) to provide the ester. In another preferred embodiment, GABA analogs can be reacted with an alkyl halide in the presence of a base to provide the ester. Other Methods for converting GABA analogs to esters or thioesters are well within the purview of one of ordinary skill in the art given the references provided herein.

Scheme 1

As illustrated above in Scheme 1, carboxylic acids can be coupled directly to the terminal amino (or hydroxyl) group of the GABA analogone derivatives (6) to provide adducts (7). Reagents for carrying out this reaction are well known to those skilled in the art and include, but are not limited to, carbodiimides, aminium salts, phosphonium salts, etc. In another embodiment, the reaction of carboxylic acid derivatives such as acyl chlorides, symmetrical anhydrides or mixed anhydrides with GABA analogs (6) in the presence of a base (e.g., hydroxide, tertiary amines, etc.) can be used to (7) synthesize.

Scheme 2

As illustrated in Scheme 2, GABA analogous derivatives (6) can be converted to carbamates (8) by treatment with various carbonic acid derivatives in the presence of a base (e.g., hydroxide, tertiary amines, etc.). In another embodiment, the well known addition of alcohols to isocyanates (9) or (10) can be used to synthesize (8).

Scheme 3

As illustrated in Scheme 3, GABA analogous derivatives (6) can be converted to thioamides (11) by reaction with thioacids in the presence of coupling agents. Reagents for carrying out this reaction are well known to those skilled in the art and include, but are not limited to, carbodiimides, aminium salts, phosphonium salts, etc. Alternatively, the reaction of thioacid derivatives such as thioacyl chlorides, symmetrical anhydrides or mixed anhydrides with (6) in the presence of a base (e.g., hydroxide, tertiary amines, etc.) can be used to synthesize thioamides (11) , In still another method, amides (7) can be converted to thioamides (11) by heating in the presence of phosphorus pentasulfide (if n = 0).

The thiocarbamates (12) and (13) can be prepared by reaction of the corresponding thiocarbonate derivatives (ie P = O, Q = S or P = S, Q = 0), where W is chloride, imidazolyl or 4-nitrophenoxy, with GABA- Analogous derivatives (6) are synthesized in the presence of a base. Thiocarbamates (13) can also be formed by reaction of a thiol with isocyanates (9) or (10). Dithiocarbamates (14) (P = S, Q = S) can be prepared by reacting GABA analogue derivatives (6) with the dithiocarbonate derivative (ie, P and Q = S) where W is chloride, imidazolyl or 4-nitrophenoxy, in the presence of a base (see Scheme 4).

Scheme 4

A method of synthesizing the compounds of formula (IV) is illustrated in Scheme 5.

Scheme 5

The chloroformate (15) is treated with an aromatic leaving group such as p-nitrophenol in the presence of a base to provide the p-nitrophenyl carbonate (16). Halide exchange provides the iodide (17) which is reacted with a metal or tetraalkylammonium salt of a carboxylic acid to provide compound (18). Treatment of (18) with the GABA analog derivative (19), optionally in the presence of trimethylsilyl chloride, yields a compound of formula (IV). Methods for preparing related acyloxyalkyl carbamate compounds have been described in the art (Alexander, U.S. Patent No. 4,760,057 ; Alexander, U.S. Patent No. 4,916,230 ; Alexander, U.S. Patent No. 5,466,811 ; Alexander, U.S. Patent No. 5,684,018 ).

In another embodiment, compounds of formula (IV) can be prepared stepwise from the carbonate (18) as illustrated in Scheme 6. Here, reaction of (18) with an α-amino acid (20), optionally protected as an ester, provides the intermediate (21) which, after deprotection (if necessary), provides compound (22), which is then purified using common peptide coupling reagents available in the United States The art is well known, coupled to the GABA analog (23).

Scheme 6

Another method of synthesizing the compounds of formula (IV) proceeds via the carbonylation of the GABA analog derivative (19) to an intermediate carbamic acid species which is trapped by an in situ alkylation reaction in a process of the methods disclosed in the art (Butcher, Synlett. 1994, 825-6; Ferres et al. U.S. Patent 4,036,829 ). Carbon dioxide gas is bubbled into a solution containing (19) and a base (eg, Cs ₂ CO ₃ , Ag ₂ CO _3, or AgO) in a solvent such as DMF or NMP. The activated halide is optionally added in the presence of iodide ions as catalyst and the carbonylation is continued until the reaction is complete. This process is illustrated in Scheme 7 for the preparation of the compounds of formula (IV) from the halide (24).

Scheme 7

In another embodiment, compounds of formula (IV) can be prepared stepwise as illustrated in Scheme 8. Carbonylation and alkylation of the carboxyl-protected α-amino acid (20) provides intermediate (21), which after deprotection is coupled to the GABA analog (23) as described in Scheme 6 above.

Scheme 8

Yet another method of synthesizing the compounds of formula (IV) is based on the oxidation of ketocarbamate derivatives of GABA analogs (Gallop et al. U.S. Patent No. 6,927,036 entitled "Methods for Synthesis of Prodrugs from 1-Acyl-Alkyl Derivatives and Compositions Thereof"("Process for the synthesis of prodrugs from 1-acyl-alkyl derivatives and compositions thereof"). As illustrated in Scheme 9, oxidation of the ketocarbamate (25) provides compounds of formula (IV). Preferred solvents include, but are not limited to, t-butanol, diethyl ether, acetic acid, hexane, dichloroethane, dichloromethane, ethyl acetate, acetonitrile, methanol, chloroform and water. In general, the oxidizing agent may be an organism (eg yeast or bacteria) or a chemical reagent (eg. an enzyme or peroxide). Preferred oxidizing agents include those which have been successfully used in Baeyer-Villager oxidations of ketones to esters or lactones (Strukul, Angew Chem, Int. Ed., 1998, 37, 1198, Renz et al., Eur. Org Chem 1999, 737, Beller et al., Transition Metals in Organic Synthesis, Chapter 2, Wiley VCH, Stewart, Current Organic Chemistry, 1998, 2, 195, Kayser et al., Synlett, 1999, 1, 153).

Scheme 9

Other compounds may be amenable to synthesis from the corresponding ketocarbamate derivative via this Baeyer-Villiger type oxidation, provided that they contain no chemical functionality that is susceptible to decomposition or other conversion under the reaction conditions.

Ketocarbamates (25) can be prepared from the corresponding α-hydroxy ketone compounds (26) either directly via reaction with isocyanate (9) or by first converting the α-hydroxy ketone compound to a haloformate or activated carbonate intermediate (27) and then to compound (19), as illustrated in Scheme 10.

Scheme 10

In another embodiment, the ketocarbamate (25) may be prepared stepwise, but the α-amino acid carbamate (28) following the coupling procedures described above, as illustrated in Scheme 11.

Scheme 11

Note that a method for preparing isocyanate derivatives of GABA analogs (ie compounds (9)) used in Scheme 10 above starts with the corresponding six-membered anhydride (29) as illustrated in Scheme 12. The anhydride ring is opened by reaction with an alcohol or thiol nucleophile to yield the carboxylic acid (30). This compound becomes either the intermediate acyl azide in a two-step sequence (ie, first activation of the carboxyl group as a mixed anhydride, acyl halide or synthetic equivalent and then azide replacement) or directly (eg, by treatment with Ph ₂ P (O) N ₃ ) transformed. Curtius rearrangement of the acyl azide intermediate by thermolysis in a suitable solvent (eg, toluene) at a temperature between 0 ° C to 120 ° C yields the isocyanate (9). Optionally, the isocyanate is not isolated, but rather is generated in situ and quenched by reaction with the α-hydroxyketone (26) to provide the desired product (25).

Scheme 12

A method of synthesizing the oxodioxolenylmethylcarbamate prodrugs (36) is disclosed in Scheme 13. The hydroxy ketone (31) is treated with phosgene or carbonyldiimidazole in the presence of a base to yield the cyclic carbonate (32). Radical bromination with N-bromosuccinimide and azoisobutyronitrile provides the bromide (33), which is converted to the alcohol (34). The alcohol (34) is converted to the dicarbonate (35) by reaction with 4-nitrophenyl chloroformate, which is then reacted with the GABA analogue derivatives (19) to provide the prodrugs (36). In another embodiment, reaction of compound (34) with isocyanate (9) provides compound (36) where n is 0.

Scheme 13

The prodrugs (41) can be synthesized by the method disclosed in Scheme 14. The carboxylic acid (37) is coupled to the alcohol (38) (e.g., dicyclohexylcarbodiimide and pyridine) to provide the ester (39). The ester (39) is converted to the activated carbonate (40) by reaction with 4-nitrophenyl chloroformate, which is then reacted with the GABA analog derivative (19) to provide the prodrug (41).

Scheme 14

Enamine prodrugs such as (43) can be synthesized simply by reacting activated carbonyl compounds (42) with GABA analogue derivatives (19) (where R ¹⁶ = H), optionally in the presence of a secondary amine catalyst, under dehydration conditions, as shown in Scheme 15 ,

Scheme 15

The compounds (III) can be synthesized by the route illustrated in Scheme 16. Reaction of the GABA analogue (23) with an α-activated ester derivative (44) provides the aminoester (45). The amino group of (45) is blocked by acylation to afford (46) (eg, using the procedure described above), and the free acid is esterified under standard conditions to afford the diester (47). Dieckmann condensation followed by decarboxylation yields the ketone (48). Peroxyacid oxidation then provides the lactone (III).

Scheme 16

Imine prodrugs (II) can be synthesized by treating ketones or ketone equivalents (49) with GABA analogue derivatives (50) under dehydration conditions, as shown in Scheme 17.

Scheme 17

Phosphorus prodrugs can be synthesized by conventional methods known in the art. Similarly, prodrugs with S-N linkage can be synthesized using methods described in the art.

4.4 Therapeutic applications of the compounds of the invention

A compound and / or composition of the invention can be administered to a patient, preferably a human, suffering from epilepsy, depression, anxiety, psychosis, fainting, hypokinesia, cranial distress, neurodegenerative disorders, panic, pain (especially neuropathic pain and muscular and skeletal pain ), Inflammatory diseases (ie arthritis), insomnia, gastrointestinal disorders or alcohol withdrawal syndrome. Further, in certain cases, the compounds and / or compositions of the invention are administered to a patient, preferably a human, as a preventive measure against various disorders or conditions. Thus, the compounds and / or compositions of the invention may be administered to a patient with a predisposition to epilepsy, depression, anxiety, psychosis, fainting, hypokinesia, craniomyopathy, neurodegenerative disorders, panic, pain (especially neuropathic pain and muscular and skeletal pain), inflammatory diseases (ie Arthritis), insomnia, gastrointestinal disorders and alcohol withdrawal syndrome as a preventative measure. Thus, the compounds and / or compositions of the invention may be used to prevent one disease or condition and, at the same time, to treat one another (e.g., prevent psychosis while treating gastrointestinal disorders; prevent neuropathic pain; an alcohol withdrawal syndrome is treated).

The suitability of the compounds and / or compositions of the invention in treating epilepsy, depression, anxiety, psychosis, fainting, hypokinesia, cranial disorders, neurodegenerative disorders, panic, pain (especially neuropathic pain and muscular and skeletal pain), inflammatory diseases (ie arthritis), Insomnia, gastrointestinal diseases and alcohol withdrawal syndrome can be determined by methods described in the art (See, e.g., Satzinger et al. U.S. Patent No. 4,024,175 ; Satzinger et al. U.S. Patent No. 4,087,544 ; Woodruff, U.S. Patent No. 5,084,169 ; Silverman et al. U.S. Patent No. 5,563,175 ; Singh, U.S. Patent No. 6,001,876 ; Horwell et al. U.S. Patent No. 6,020,370 ; Silverman et al. U.S. Patent No. 6,028,214 ; Horwell et al. U.S. Patent No. 6,103,932 ; Silverman et al. U.S. Patent No. 6,117,906 ; Silverman, International Disclosure No. WO 92/09560 ; Silverman et al., International Disclosure No. WO 93/23383 ; Horwell et al., International Disclosure No. WO 97/29101 , Horwell et al., International Disclosure No. WO 97/33858 ; Horwell et al., International Disclosure No. WO 97/33859 ; Bryans et al., International Disclosure No. WO 98/17627 ; Guglietta et al., International Disclosure No. WO 99/08671 ; Bryans et al., International Disclosure No. WO 99/21824 ; Bryans et al., International Disclosure No. WO 99/31057 ; Magnus-Miller et al., International Disclosure No. WO 99/37296 ; Bryans et al., International Disclosure No. WO 99/31075 ; Bryans et al., International Disclosure No. WO 99/61424 ; Pande, International Disclosure No. WO 00/23067 ; Bryans, International Disclosure No. WO 00/31020 ; Bryans et al., International Disclosure No. WO 00/50027 and Bryans et al., International Disclosure No. WO 02/00209 ). The compounds and / or compositions of the invention may be used to treat or prevent epilepsy, depression, anxiety, psychosis, fainting, hypokinesia, cranial disorders, neurodegenerative disorders, panic, pain (especially neuropathic pain and muscular and skeletal pain), inflammatory diseases (ie, arthritis). , Insomnia, gastrointestinal diseases and alcohol withdrawal syndrome by methods described in the art (see above references). Thus, it is well within the purview of those skilled in the art to use the compounds and / or compositions of the invention for treating or preventing epilepsy, depression, anxiety, psychosis, fainting, hypokinesia, cranial distress, neurodegenerative disorders, panic, pain (especially neuropathic pain and muscular and skeletal pain ), Inflammatory diseases (ie arthritis), insomnia, gastrointestinal disorders and alcohol withdrawal syndrome to be tested and used.

4.5 Therapeutic / prophylactic administration

The compounds and / or compositions of the invention may be advantageously used in human medicine. As previously described in Section 4.4 above, the compounds and / or compositions of the invention are for the treatment or prevention of epilepsy, depression, anxiety, psychosis, fainting, hypokinesia, cranial distress, neurodegenerative disorders, panic, pain (especially neuropathic pain and muscle and skeletal pain), inflammatory diseases (ie arthritis), insomnia, gastrointestinal disorders or alcohol withdrawal syndrome.

When used to treat or prevent the above diseases or conditions, the compounds and / or compositions of the invention may be administered or used alone or in combination with other agents. The compounds and / or compositions of the invention may also be administered or used alone or in conjunction with other pharmaceutically active agents, including other compounds of the invention.

The present invention provides compounds and compositions for use in methods of treatment and prophylaxis by administering to a patient a therapeutically effective amount of a composition or compound of the invention. The patient may be an animal, more preferably a mammal, and most preferably a human.

The present compounds and / or compositions of the invention comprising one or more compounds of the invention are preferably administered orally. The compounds and / or compositions of the invention may also be administered by any other convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.). Administration can be systemic or local. Various delivery systems (e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, etc.) are known which can be used to administer a compound and / or composition of the invention. The methods of administration include, but are not limited to, intradermally, intramuscularly, intraperitoneally, intravenously, subcutaneously, intranasally, epidurally, orally, sublingually, intranasally, intracerebrally, intravaginally, transdermally, rectally, by inhalation or topically, especially to the ears, nose, eyes or skin are not limited to this.

In particularly preferred embodiments, the compounds and / or compositions of the invention may be delivered via sustained release systems, preferably sustained release oral systems. In one embodiment, a pump may be used (see Langer, supra; Sefton, 1987, CRC Crit Ref Biomed Eng 14: 201; Saudek et al., 1989, N. Engl. J. Med. 321: 574). ,

In another embodiment, polymeric materials may be used (see "Medical Applications of Controlled Release," Langer and Wise (eds.), CRC Press, Boca Raton, Florida. (1974); "Controlled Drug Bioavailability," Drug Product Design and Performance Smolen and Ball (ed.), Wiley, New York (1984); Ranger and Peppas, 1983, J. Macromol, Sci., Rev. Macromol, Chem., 23: 61; see also Levy et al., 1985, Science 228 : 190; During et al., 1989, Ann. Neurol. 25: 351; Howard et al., 1989, J. Neurosurg. 71: 105). In a preferred embodiment, sustained release polymeric sustained-release materials are used. Preferred polymers include sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and hydroxyethylcellulose (most preferably hydroxypropylmethylcellulose). Other preferred cellulose ethers have been described (Alderman, Int., J. Pharm. Tech. & Prod. Mfr., 1984, 5 (3) 1-9). The factors which affect drug release are well known to those skilled in the art and have been described in the art (Bamba et al., Int. J. Pharm., 1979, 2, 307).

In another embodiment, enteric sustained release oral compositions may be used. Preferred coating materials include polymers having a pH-dependent solubility (ie, pH-controlled release), polymers having a slow or pH-dependent swelling, dissolution or erosion rate (ie, time-controlled release), polymers degraded by enzymes, ( ie, enzyme controlled release) and polymers that form solid layers that are destroyed by a pressure increase (ie, pressure controlled release).

In yet another embodiment, sustained-release oral delivery osmotic delivery systems are used (Verma et al., Drug Dev. Ind. Pharm., 2000, 26: 695-708). In a preferred embodiment, osmotic OROS ^™ devices are used for sustained release oral delivery devices (Theeuwes et al. U.S. Patent No. 3,845,770 ; Theeuwes et al. U.S. Patent No. 3,916,899 ).

In yet another embodiment, a controlled release system may be applied near the target of the compounds and / or composition of the invention, thus requiring only a fraction of the systemic dose (see, e.g., Goodson in "Medical Applications of Controlled Release ", Supra, Vol. 2, pp. 115-138 (1984)). Other controlled release systems discussed in Langer, 1990, Science 249: 1527-1533 can also be used.

The compounds and / or compositions of the invention provide gabapentin after in vivo administration to a patient. Although not wishing to be bound by theory, the pro-unit or pro-units of the compounds and / or compositions of the invention may be cleaved either chemically and / or enzymatically. One or more enzymes present in the stomach, intestinal lumen, intestinal tissue, blood, liver, brain, or any other suitable mammalian tissue may enzymatically cleave the pro-unit or pro-units of the compounds and / or compositions of the invention. The mechanism of cleavage is not important to the present invention. Preferably, the GABA analogs formed by cleavage of the prodrugs from the compounds of the invention do not contain appreciable amounts of lactam contaminant (preferably less than 0.5%, more preferably less than 0.2%, by weight) most preferably less than 0.1% by weight). The extent of release of lactam impurity from the prodrugs of this invention can be evaluated using standard in vitro analytical methods.

Although not wishing to be bound by theory, the pro-unit or pro-units of the compounds and / or compositions of the invention may be prepared prior to absorption through the gastrointestinal tract (eg, within the stomach or intestinal lumen) and / or after absorption through the gastrointestinal tract (e.g., in intestinal tissue, blood, liver, or other suitable mammalian tissue). If the pro-unit or pro-units of the compounds of the invention are cleaved prior to absorption through the gastrointestinal tract, the resulting GABA analog can be absorbed into the systemic circulation in a conventional manner (e.g., via the small neutral amino acid transporter located in the small intestine) become. If the pro-unit or pro-units of the compounds of the invention are cleaved after absorption through the gastrointestinal tract, these GABA-analog prodrugs may have the opportunity, either by passive diffusion, active transport or by both passive and active processes in the systemic circulation to be absorbed.

If the pro-unit or pro-units of the compounds of the invention are cleaved after absorption through the gastrointestinal tract, these GABA analog prodrugs may have the opportunity to be absorbed from the colon into the systemic circulation. In this situation, the compounds and / or compositions of the invention are preferably administered as sustained release systems. In a preferred embodiment, the compounds and / or compositions of the invention are delivered by sustained release oral administration. In this embodiment, the compounds and / or compositions of the invention are preferably administered twice a day (more preferably once a day).

4.6 Compositions of the invention

The present compositions contain a therapeutically effective amount of one or more compounds of the invention, preferably in purified form, together with a suitable amount of a pharmaceutically acceptable vehicle, wherein the form is provided for proper administration to a patient. When administered to a patient, the compounds of the invention and the pharmaceutically acceptable vehicles are preferably sterile. Water is a preferred vehicle when a compound of the invention is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be used as liquid vehicles, especially for injectable solutions. Suitable pharmaceutical vehicles also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skimmed milk, glycerine, propylene glycol, water, ethanol and the like , The present compositions may also contain minor amounts of wetting or emulsifying agents or pH buffering agents, if desired. In addition, auxiliaries, stabilizers, thickeners, lubricants and colorants can be used.

In one embodiment, the compositions of the invention are free of lactam by-products formed by intramolecular cyclization. In a preferred embodiment, the compositions of the invention are stable upon prolonged storage (preferably more than one year) without substantial lactam formation (preferably less than 0.5% by weight lactam, more preferably less than 0.2% by weight lactam, am most preferably less than 0.1% by weight lactam).

Pharmaceutical compositions comprising a compound of the invention can be prepared by conventional mixing, dissolving, granulating, dragee-making, triturating, emulsifying, encapsulating, entrapping or freeze-drying processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients or excipients which facilitate the processing of the compounds of the invention into preparations which can be used pharmaceutically. The correct formulation depends on the chosen route of administration.

The present compositions may take the form of solutions, suspensions, emulsions, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions or any other form containing is suitable for use. In one embodiment, the pharmaceutically acceptable vehicle is a capsule (see, e.g., Grosswald et al. U.S. Patent No. 5,698,155 ). Other examples of suitable pharmaceutical vehicles have been described in the art (see Remington's Pharmaceutical Sciences, Philadelphia College of Pharmacy and Science, 17th Edition, 1985). Preferred compositions of the invention are formulated for oral delivery, especially sustained release oral administration.

Oral compositions can be in the form of, for example, tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups or elixirs. Orally administered compositions may contain one or more optional agents, for example sweeteners such as fructose, aspartame or saccharin, flavoring agents such as peppermint, wintergreen oil or cherry, colorants and preservatives to provide a pharmaceutically palatable preparation. In addition, the compositions, when in tablet or pill form, may be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a prolonged period of time. Selectively permeable membranes that surround an osmotically-active driving compound are also suitable for orally administered compounds and compositions of the invention. In these later platforms, liquid from the environment surrounding the capsule is absorbed by the drive connection which swells, displacing the agent or agent composition through an opening. These delivery platforms can provide a substantially zero order delivery profile as opposed to the tipped profiles of the immediate release formulations. A time delay material such as glycerol monostearate or glyceryl stearate may also be used. Oral compositions may include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Such vehicles are preferably of pharmaceutical grade.

For oral liquid preparations, such as suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, saline, alkylene glycols (eg, propylene glycol), polyalkylene glycols (eg, polyethylene glycol), oils, alcohols, weakly acidic buffers between pH 4 and pH 6 (eg, acetate, citrate, ascorbate between about 5 mM to about 50 mM), etc. In addition, flavorings, preservatives, coloring agents, bile salts, acylcarnitines and the like may be added.

Compositions for administration by other routes may also be considered. For buccal administration, the compositions may take the form of tablets, lozenges, etc. formulated in a conventional manner. Liquid drug formulations suitable for use with nebulizers and liquid spray devices and EHD aerosol devices will typically include a compound of the invention with a pharmaceutically acceptable vehicle. Preferably, the pharmaceutically acceptable vehicle is a liquid such as alcohol, water, polyethylene glycol or a perfluorocarbon. Optionally, another material may be added to alter the aerosol properties of the solution or suspension of the compounds of the invention. Preferably, this material is liquid, such as an alcohol, glycol, polyglycol or a fatty acid. Other methods for formulating liquid drug solutions or suspensions suitable for use in aerosol devices are known to those skilled in the art (See, e.g., Biesalski, et al. U.S. Patent No. 5,112,598 ; Biesalksi, U.S. Patent No. 5,556,611 ). A compound of the invention may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g. Conventional suppository bases such as cocoa butter or other glycerides. In addition to the formulations described above, a compound of the invention may also be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, a compound of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

A compound of the invention may be included in any of the above-described formulations as the free acid, pharmaceutically acceptable salt, solvate or hydrate. Pharmaceutically acceptable salts substantially retain the efficacy of the free acid, can be prepared by reaction with bases, and tend to be more soluble in aqueous and other protic solvents than the corresponding free acid form.

4.7 Methods of use and doses

A compound of the invention or compositions thereof will generally be used in an amount effective to achieve its intended purpose. For use with Treating or preventing diseases or conditions such as epilepsy, depression, anxiety, psychosis, fainting, hypokinesia, cranial disorders, neurodegenerative disorders, panic, pain (especially neuropathic pain and muscular and skeletal pain), inflammatory diseases (ie arthritis), insomnia, gastric disorders Intestinal disorders or alcohol withdrawal syndrome are administered or used the compounds of the invention or compositions thereof in a therapeutically effective amount.

The amount of a compound of the invention which will be effective in the treatment of a particular condition or condition disclosed herein will depend on the nature of the condition or condition and can be determined by standard clinical techniques known in the art, such as previously described. In addition, in vitro or in vivo studies may optionally be used to help identify optimal dosage ranges. The administered amount of a compound of the invention will of course depend, among other factors, on the patient being treated, the weight of the patient, the severity of the discomfort, the mode of administration and the judgment of the prescribing physician.

For example, the dosage may be delivered in a pharmaceutical composition by a single administration, by multiple applications or controlled release. Preferably, the compounds of the invention are delivered by sustained release oral administration. Preferably, the compounds of the invention are administered twice a day (more preferably once a day). The dosage may be intermittent, may be provided alone or in conjunction with other drugs and may be continued as long as it is necessary for an effective treatment of the disease state or condition.

Suitable dosage ranges for oral administration depend on the potency of the parent GABA analogue drug. Because the GABA analog is gabapentin, typical daily doses of the parent drug in adult patients are 900 mg / day to 3600 mg / day and the dose of gabapentin prodrug can be adjusted to provide an equivalent molar amount of gabapentin. The dosage ranges can be readily determined by methods known to those skilled in the art.

The compounds of the invention are preferably tested in vitro and in vivo for the desired therapeutic or prophylactic activity prior to use in humans. For example, in vitro assays can be used to determine whether administration of a particular compound of the invention or a combination of compounds of the invention to reduce convulsion is preferred. Using animal model systems, it can also be shown that the compounds of the invention are effective and safe.

Preferably, a therapeutically effective dose of a compound of the invention described herein will provide a therapeutic benefit without causing substantial toxicity. The toxicity of the compounds of the invention can be determined using standard pharmaceutical procedures and can be readily determined by one skilled in the art. The dose ratio between toxic and therapeutic effect is the therapeutic index. A compound of the invention will preferably exhibit particularly high therapeutic indices in treating diseases and conditions. The dosage of a compound of the invention described herein will preferably be within a range of circulating concentrations that include an effective dose with little or no toxicity.

4.8. combination therapy

In certain embodiments of the present invention, the compounds of the invention may be used in combination therapy with at least one other therapeutic agent. The compound of the invention and the therapeutic agent may act additive or more preferably synergistic. Preferably, a composition comprising a compound of the invention is administered concomitantly with the administration of another therapeutic agent which may be part of the same composition as the compound of the invention or another composition. In another embodiment, a composition comprising a compound of the invention is administered prior to or subsequent to administration of another therapeutic agent.

5. Examples

The invention will be further defined by reference to certain of the following examples which detail the preparation of the compounds and compositions of the invention and studies on the use of the compounds and compositions of the invention.

AIBN

= 2,2'-Azobis(isobutyronitril)

Atm

= Atmosphäre

Boc

= tert.-Butyloxycarbonyl

Cbz

= Carbobenzyloxy

CPM

= Zählimpulse pro Minute

DCC

= Dicyclohexylcarbodiimid

DMAP

= 4-N,N-Dimethylaminopyridin

DMEM

= Dulbecco's Minimum Eagle Medium

DMF

= N,N-Dimethylformamid

DMSO

= Dimethylsulfoxid

Fmoc

= 9-Fluorenylmethyloxycarbonyl

g

= Gramm

h

= Stunde

HBSS

= Hanks gepufferte Kochsalzlösung

l

= Liter

LC/MS

= Flüssigkeitschromatographie/Massenspektroskopie

M

= molar

min

= Minute

ml

= Milliliter

mmol

= Millimol

NBS

= N-Bromsuccinimid

NHS

= N-Hydroxysuccinimid

PBS

= Phosphat-gepufferte Kochsalzlösung

THF

= Tetrahydrofuran

TFA

= Trifluoressigsäure

TMS

= Trimethylsilyl

μl

= Mikroliter

μM

= mikromolar

v/v

= Volumen zu Volumen

In the examples below, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.

AIBN

= 2,2'-azobis (isobutyronitrile)

atm

= Atmosphere

Boc

= tert-butyloxycarbonyl

Cbz

= Carbobenzyloxy

CPM

= Counts per minute

DCC

= Dicyclohexylcarbodiimide

DMAP

= 4-N, N-dimethylaminopyridine

DMEM

= Dulbecco's Minimum Eagle Medium

DMF

= N, N-dimethylformamide

DMSO

= Dimethyl sulfoxide

Fmoc

= 9-fluorenylmethyloxycarbonyl

G

= Grams

H

= Hour

HBSS

= Hank's buffered saline

l

= Liter

LC / MS

= Liquid chromatography / mass spectroscopy

M

= molar

min

= Minute

ml

= Milliliters

mmol

= Millimoles

NBS

= N-bromosuccinimide

NHS

= N-hydroxysuccinimide

PBS

= Phosphate-buffered saline

THF

= Tetrahydrofuran

TFA

= Trifluoroacetic acid

TMS

= Trimethylsilyl

ul

= Microliters

uM

= micromolar

v / v

= Volume to volume

(COMPARATIVE) EXAMPLE 1

1 - {[(α-Pivaloyloxymethoxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (51)

Step A: Chloromethyl p-nitrophenyl carbonate (52)

p-Nitrophenol (100 g, 0.72 mol) was dissolved in anhydrous tetrahydrofuran (3 L) and stirred vigorously. Chloroformic acid chloroformate (70 mL, 0.79 mol) was added to this solution at room temperature followed by triethylamine (110 mL). After stirring for 1 h, the reaction mixture was filtered and the filtrate was concentrated and then diluted with ethyl acetate (1 L). The organic solution was washed with 10% potassium carbonate solution (3 × 500 ml), 1N HCl (2 × 300 ml) and brine (2 × 300 ml) and dried over anhydrous sodium sulfate. Removal of the solvent gave 157 g (95%) of the title compound (52) as a solid. The compound was unstable for LC-MS. ¹ H-NMR _(CDCl3, 400 MHz): 5.86 (s, 2H), 7.44 (d, J = 9 Hz, 2H), 8.33 (d, J = 9 Hz, 2H).

Step B: Iodomethyl p-nitrophenyl carbonate (53)

Chloromethyl p-nitrophenyl carbonate (52) (100 g, 0.43 mol), sodium iodide (228 g, 1.30 mol) and 50 g of dried molecular sieve (4 Å) were added with mechanical stirring to 2 L of acetone under nitrogen. The resulting mixture was stirred at 40 ° C for 5 hours (monitored by ¹ H-NMR). Upon completion, the solid materials were removed by filtration and the solvent became under reduced pressure away. The residue was redissolved in dichloromethane (1 L) and washed twice with saturated aqueous sodium carbonate solution (300 mL), followed by water (300 mL). The organic phase was separated and dried over anhydrous sodium sulfate. Removal of the solvent afforded, after standing, 123.6 g (89%) of the title compound (53) as a solid. It has been found that the compound is unstable for LC-MS. ¹ H-NMR _(CDCl3, 400 MHz): 6.06 (s, 2H), 7.42 (d, J = 9 Hz, 2H), 8.30 (d, J = 9 Hz, 2H). ¹³ C-NMR (CDCl _3, 100 MHz): 155.1; 151.0; 146.0; 125.8; 125.7; 121.9; 33.5.

Step C: Silver Pivalate (54)

Pivalic acid (50 g, 0.49 mol) was dissolved in acetonitrile (1.3 L) followed by addition of silver oxide (70 g, 0.29 mol) with vigorous stirring. Then, 660 ml of water was added under nitrogen. The resulting suspension was stirred for 1 hour at 70 ° C in the dark. After filtration through a celite pad, removal of the solvent afforded 86 g (82%) of the title compound (54) as a light white solid, which was used in the next reaction without further purification.

Other silver salts described in this application are prepared following similar procedures.

Step D: p-nitrophenyl pivaloyloxymethyl carbonate (55)

To a solution of iodomethyl p-nitrophenyl carbonate (53) (62 g, 0.19 mol) in anhydrous toluene (1 L) was added silver pivalate (80 g, 0.38 mol). After stirring for 3 hours at 55 ° C under nitrogen, the reaction mixture was allowed to cool to room temperature and filtered through a celite pad. The filtrate was washed with 10% potassium carbonate solution (500 ml). Removal of the solvent afforded 43 g (75%) of the title compound (55) as a yellow oil. ¹ H-NMR _(CDCl3, 400 MHz): 1.25 (s, 9H), 5.88 (s, 2H), 7.40 (d, J = 9 Hz, 2H), 8.29 (d, J = 9 Hz, 2H). ¹³ C-NMR (CDCl _3, 100 MHz): 177.0; 155.3; 151.6; 145.8; 125.6; 121.9; 83.1; 39.1; 27.0.

Step E: 1 - {[(α-Pivaloyloxymethoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid (51)

The free base gabapentin (24 g, 0.14 mol) was slurried in anhydrous dichloromethane (100 mL) and then treated with chlorotrimethylsilane (18.6 mL, 0.28 mol) and triethylamine (10 mL, 0.15 mol), respectively , The resulting suspension was heated with stirring until complete dissolution of any solid was achieved. The above gabapentin solution was added via an addition funnel with gentle reflux and mechanical stirring of a solution of p-nitrophenyl pivaloyloxymethyl carbonate (55) (20 g, 67 mmol) and triethylamine (10 mL, 0.15 mol) in dichloromethane (100 mL). added under nitrogen. The resulting yellow solution was stirred for 1.5 hours. Upon completion (monitored by ninhydrin staining), the mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate (500 ml) and washed with 1N HCl (3 × 100 ml) and brine (2 × 100 ml) and dried over anhydrous sodium sulfate. After removing the solvent, the crude product was dissolved in ethanol (300 ml) and then 1 g of 5% Pd / C was added. The resulting mixture was shaken for 15 minutes under 50 psi hydrogen atmosphere and then filtered through a celite pad. After concentration, the residue was dissolved in ethyl acetate, washed with 5% H ₂ SO ₄ and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the residue was purified by chromatography on silica gel (4: 1 hexane: ethyl acetate) to afford 15 g (68%) of the title compound (51) as a solid. Mp: 79-81 ° C; ¹ H-NMR _(CDCl3, 400 MHz): 1.21 (s, 9H), 1.3-1.5 (m, 10H), 2.32 (s, 2H), 3.26 (s, 2H ), 5.33 (m, 1H), 5.73 (s, 2H). ¹³ C-NMR _(CDCl3, 400 MHz): 21.7; 26.2; 27.3; 34.3; 38.2; 39.2; 80.6; 155.9; 176.8; 178.0. MS (ESI) m / z 328.36 (M-H) ^- , 330.32 (M + H) ⁺ , 352.33 (M + Na) ⁺ .

(COMPARISON) EXAMPLE 2

1 - {[(α-acetoxyethoxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (56)

Step A: 1-chloroethyl-p-nitrophenyl carbonate (57)

To an ice-cold reaction mixture containing p-nitrophenol (1.39 g, 10 mmol) and pyridine (0.81 g, 10 mmol) in dichloromethane (60 mL) was added chloroformic acid 1-chloroethyl ester (1.2 mL, 11 mmol ) was added. The mixture was stirred at 0 ° C for 30 minutes and then at room temperature for 1 hour. After removing the solvent under reduced pressure, the residue was dissolved in ether, washed with water, 10% citric acid and water. The ether phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure Evaporated to give 2.4 g (97%) of the title compound (57) as a cream solid. ¹ H-NMR _(CDCl3): 1.93 (d, 3H), 6.55 (q, 1H), 7.42 (d, 2H), 8.28 (d, 2H).

Step B: α-Acetoxyethyl p-nitrophenyl carbonate (58)

A mixture of 1-chloroethyl-p-nitrophenyl carbonate (57) (0.5 g, 2 mmol) and mercuric acetate (1.5 g, 4.4 mmol) in acetic acid (15 ml) was stirred at room temperature for 24 hours. After removing the acetic acid under reduced pressure, the residue was dissolved in ether and washed with water, 0.5% (v / v) aqueous NaHCO ₃ solution and water. The ether phase was dried over Na ₂ SO ₄ and concentrated to dryness. Chromatography of the resulting residue on silica gel (hexane: ethyl acetate (95: 5)) gave 0.45 g (84%) of the title compound (58). ¹ H-NMR _(CDCl3, 400 MHz): 1.55 (d, J = 5.6 Hz, 3H), 2.07 (s, 3H), 6.78 (q, J = 5.6 Hz, 1H), 7.36 (d, J = 9.6 Hz, 2H), 8.22 (d, J = 9.6 Hz, 2H).

Step C: 1 - {[(α-Acetoxyethoxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (56)

To a mixture containing gabapentin (633 mg, 3.7 mmol) and triethylamine (1.03 mL, 7.4 mmol) in dichloromethane (20 mL) was added trimethylchlorosilane (0.93 mL, 7.4 mmol) and the mixture was stirred until a clear solution was formed. A solution containing α-acetoxyethyl-p-nitrophenyl carbonate (58) (1 g, 3.7 mmol) in dichloromethane (10 ml) was then added and the resulting mixture was stirred for 30 minutes. The reaction mixture was washed with 10% citric acid (20 ml) and the organic phase was separated. The aqueous phase was further extracted with ether (3 x 10 ml) and the combined organic extracts were dried over MgSO ₄ . After filtration, the organic solvent was removed under reduced pressure. Chromatography of the resulting residue on silica gel (hexane: ethyl acetate (4: 1)) gave 700 mg (63%) of the title compound (56). ¹ H-NMR _(CDCl3, 400 MHz): 1.27 to 1.60 (m, 10H), 1.55 (d, 3H), 2.08 (s, 3H), 2.38 (s, 2H ), 3.25 (m, 2H), 5.31 (t, 1H), 6.81 (q, 1H). MS (ESI) m / z 302,22 (M + H) ⁺ . The acid form was quantitatively converted to the corresponding sodium salt by dissolving in water (5 ml), adding an equimolar amount of 0.5N NaHCO ₃ solution, followed by lyophilization.

(COMPARATIVE) EXAMPLE 3

1 - {[(α-Benzoyloxybenzyloxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (59)

Step A: p-Nitrophenyl-α-benzoylbenzylcarbonate (60)

To a solution of benzoin (2.0 g, 9.4 mmol) in 60 mL of CH ₂ Cl ₂ at room temperature was added DMAP (1.21 g, 9.9 mmol) or p-nitrophenyl chloroformate (1.99 g, 9.9 mmol) was added. After stirring at room temperature for 3 hours, the reaction was quenched with water and extracted with ethyl acetate / hexane (2 × 100 ml). The combined organic extracts were dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure afforded the title compound (60), which was used in the next reaction without purification.

Step B: 1 - {[(α-Benzoylbenzyloxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (61)

To a suspension of gabapentin (1.70 g, 9.9 mmol) in CH ₂ Cl ₂ at 0 ° C was added triethylamine (2.76 mL, 19.8 mmol) and TMSCl (2.51 mL, 19.8 mmol). added. The reaction mixture was then stirred for 30 minutes at room temperature. To this mixture was added compound (60) (prepared in step A above) in CH ₂ Cl _2, and the resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with dichloromethane, washed with brine, and the organic phase was dried over Na ₂ SO ₄ . After removing the solvent under reduced pressure, the residue was purified by chromatography on silica gel eluting with 5% methanol in CH ₂ Cl _{2 to give} 3.78 g of title compound (61) (90% over two steps). ¹ H-NMR _(CDCl3, 400 MHz): δ 1.48 to 1.35 (m, 10H), 2.30 (s, 2H), 3.24 (d, J = 7.2 Hz, 2H) , 5.58 (t, J = 6.8Hz, 1H), 6.85 (s, 1H), 7.50-7.33 (m, 8H), 7.93 (d, J = 7.2 Hz, 2H).

Step C: 1 - {[(α-Benzoyloxybenzyloxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid (59)

To a solution of 1 - {[(α-benzoylbenzyloxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid (61) (1.89 g, 4.6 mmol) in 40 mL of CH ₂ Cl _{2 was} added 77% mCPBA (2.07 g, 9.2 mmol) or NaHCO ₃ (0.78 g, 9.2 mmol) was added at room temperature and the resulting mixture was stirred at room temperature overnight. The reaction mixture was acidified with 10% citric acid and extracted with CH ₂ Cl ₂ . Of the The organic extract was washed with brine and dried over Na ₂ SO ₄ . After removing the solvent under reduced pressure, the residue was purified by preparative reverse phase HPLC (acetonitrile-water, 0.1% formic acid) to afford 960 mg (49%) of the title compound (59). ¹ H-NMR _(CDCl3, 400 MHz): δ 1.58 to 1.35 (m, 10H), 2.34 (s, 2H), 3.26 (dd, J = 6.8; 0.8 Hz, 2H), 5.38 (t, J = 6.8 Hz, 1H), 7.46-7.26 (m, 5H), 7.63-7.55 (m, 3H), 7.89 (s, 1H), 8.08 (dd, J = 8.8, 1.2 Hz, 2H).

(COMPARISON) EXAMPLE 4

1 - {[(α-acetoxybenzyloxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (62)

Following the procedure of Example 3 and replacing the benzoin with 1-hydroxy-1-phenylpropan-2-one afforded 300 mg of the title compound (62). ¹ H-NMR _(CDCl3, 400 MHz): δ 1.41 (m, 10H), 2.19 (s, 3H), 2.33 (s, 2H), 3.27 (dd, J = 6, 6, 1.6 Hz, 2H), 5.36 (t, J = 6.6 Hz, 1H), 7.40 (m, 3H), 7.52 (m, 2H), 7.63 (s, 1H).

(COMPARATIVE) EXAMPLE 5

1 - {[(α-benzoyloxyethoxy) carbonylaminomethyl} -1-cyclohexanoacetic acid (63)

Following the procedure of Example 3 and replacing the benzoin with 2-hydroxy-1-phenyl-1-propanone afforded 5 mg of the title compound (63). ¹ H-NMR _(CDCl3, 400 MHz): δ 1.44 to 1.36 (m, 10H), 1.62 (d, J = 5.6 Hz, 3H), 2.34 (s, 2H) , 3.24 (d, J = 6.8 Hz, 2H), 5.28 (t, J = 6.8 Hz, 1H), 7.06 (q, J = 5.6 Hz, 1H), 7 , 44 (m, 2H), 7.56 (m, 1H), 8.03 (dd, J = 8.4, 1.6 Hz, 2H).

(COMPARATIVE) EXAMPLE 6

1 - {[(1-Benzoyloxy-2-phenylethoxy) carbonyl] aminomethyl-1-cyclohexanoacetic acid (64)

Step A: 2-Phenyl- [1,3] -dithiane (65)

To a solution of benzaldehyde (10.6 g, 100 mmol) and 1,3-propanedithiol in CH ₂ Cl ₂ (150 mL) was added dropwise at room temperature BF ₃ -Et ₂ O (6.3 mL, 50 mmol) and the resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was then diluted with CH ₂ Cl ₂ , filtered and the filtrate washed with brine, saturated NaHCO ₃ and brine, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to afford a white solid, which was recrystallized from a 1: 1 mixture of ether and hexane to afford 17.0 g (87%) of the title compound (65) as white crystalline needles. ¹ H-NMR _(CDCl3, 400 MHz): δ 1.91 (m, 1H), 2.14 (m, 1H), 2.89 (m, 2H), 3.04 (m, 2H), 5 , 16 (s, 1H), 7.35-7.28 (m, 3H), 7.46 (m, 2H).

Step B: 2-Phenol-1- (2-phenyl- [1,3] -dithian-2-yl) ethanol (66)

To a solution of 2-phenyl- [1,3] -dithiane (65) (4.0 g, 20.4 mmol) in THF at -30 ° C was added a 1.6 M solution of n-butyllithium in THF (15 , 3 ml, 24.4 mmol). After stirring at -30 ° C for 30 minutes, a solution of phenylacetylaldehyde (2.45 g, 20.4 mmol) in tetrahydrofuran was added dropwise at -30 ° C. The resulting reaction mixture was stirred for a further hour at 0 ° C. The reaction was quenched with saturated NH ₄ Cl solution and extracted with ethyl acetate. The combined organic extracts were washed with saturated NH ₄ Cl solution and brine and dried over Na ₂ SO ₄ . After filtration and concentration, the crude product was purified by flash chromatography on silica gel (25% ethyl acetate in hexane) to afford 2.63 g (71%) of the title compound (66). ¹ H-NMR _(CDCl3, 400 MHz): δ 1.97 (m, 2H), 2.23 (dd, J = 4.0, 1.2 Hz, 1H), 2.43 (dd, J = 13.6, 10.2 Hz, 1H), 2.77 (m, 4H), 3.02 (d, J = 13.6 Hz, 1H), 4.07 (m, 1H), 7.44- 7.13 (m, 8H), 8.02 (dd, J = 8.4, 1.4Hz, 2H).

Step C: 2-Hydroxy-1,3-diphenylpropan-1-one (67)

To a solution of 2-phenyl-1- (2-phenyl- [1,3] -dithian-2-yl) -ethanol (66) (2.50 g, 7.9 mmol) in 100 ml of a 9: 1 mixture from acetonitrile and water was added mercury perchlorate hydrate (4.1 g, 10.3 mmol). The resulting mixture was stirred at room temperature for 5 minutes, and thin layer chromatography indicated that the reaction was complete. The mixture was diluted with ethyl acetate, filtered through a celite pad, and the filtrate was washed with saturated NaHCO _3, brine, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the crude product was purified by flash chromatography on silica gel (20% ethyl acetate in hexane), where 1, 32 g (74%) of title compound (67). ¹ H-NMR _(CDCl3, 400 MHz): δ 2.90 (dd, J = 14.4, 7.0 Hz, 1H), 3.20 (dd, J = 14.4, 4.0 Hz, 1H), 3.70 (d, J = 6.8Hz, 1H), 5.35 (m, 1H), 7.28-7.11 (m, 5H), 7.53 (m, 2H), 7.65 (m, 1H), 7.93 (d, J = 7.2 Hz, 2H).

Step D: 1 - {[(1-Benzoyloxy-2-phenylethoxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (64)

Following the procedure of Example 3 and replacing the benzoin with 2-hydroxy-1,3-diphenylpropan-1-one afforded 181 mg of the title compound (64). ¹ H-NMR _(CDCl3, 400 MHz): δ 1.45 to 1.29 (m, 10H), 2.24 (d, J = 13.6 Hz, 1H), 2.28 (d, J = 13.6 Hz, 1H), 3.22 (m, 4H), 5.26 (t, J = 6.6 Hz, 1H), 7.16 (t, J = 5.6 Hz, 1H), 7 , 33-7.25 (m, 5H), 7.40 (m, 2H), 7.57 (m, 1H), 8.02 (m, 2H).

(COMPARATIVE) EXAMPLE 7

1 - {[(1- (3-Methylbutanoyloxy) phenylethoxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (68)

Following the procedure of Example 6 and replacing the benzaldehyde in Step A with 3-methylbutyraldehyde afforded 95 mg of the title compound (68). ¹ H-NMR _(CDCl3, 400 MHz): δ 0.88-0.90 (m, 6H), 1.16 to 1.29 (m, 10H), 2.06 (m, 1H), 2, 16 (m, 2H), 2.26 (m, 2H), 3.08 (d, J = 6.8Hz, 2H), 3.19 (m, 2H), 5.22 (t, J = 6 , 8Hz, 1H), 6.93 (t, J = 6Hz, 1H), 7.31-7.23 (m, 5H).

(COMPARATIVE) EXAMPLE 8

1 - {[(α-benzoyloxybutoxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (69)

Following the procedure of Example 6 and replacing the phenylacetaldehyde in Step B with butyraldehyde afforded 240 mg of the title compound (69). ¹ H-NMR _(CDCl3, 400 MHz): δ 0.99 (t, J = 7.6 Hz, 3H), 1.52 to 1.38 (m, 12H), 1.89 (m, 2H) , 2.31 (s, 2H), 3.24 (m, 2H), 5.34 (t, J = 6.6 Hz, 1H), 6.70 (t, J = 5.6 Hz, 1H) , 7.42 (m, 2H), 7.56 (m, 1H), 8.04 (m, 2H).

(COMPARISON) EXAMPLE 9

1 - {[(α-acetoxybutoxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (70)

Following the procedure of Example 6 and replacing the benzaldehyde in Step A with acetaldehyde or replacing the phenylacetaldehyde in Step B with butyraldehyde afforded 42 mg of the title compound (70). ¹ H-NMR (CD ₃ OD, 400 MHz): δ 0.95 (m, 3H), 1.52-1.31 (m, 12H), 1.72 (m, 2H), 2.02 (s , 3H), 2.27 (s, 2H), 3.20 (s, 2H), 6.67 (t, J = 5.6 Hz, 1H).

(COMPARATIVE) EXAMPLE 10

1 - {[(α-butanoyloxybutoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid (71)

Following the procedure of Example 3 and replacing the benzoin with butyroine afforded 210 mg of the title compound (71). ¹ H-NMR _(CDCl3, 400 MHz): δ 0.93 (m, 6H), 1.37 to 1.76 (m, 16H), 2.30 (m, 4H), 3.23 (m, 2H), 5.25 (broad triplet, 1H), 6.73 (m, 1H). MS (ESI) m / z 356.45 (M-H) ⁺ .

(COMPARATIVE) EXAMPLE 11

1 - {[(α-propanoyloxyethoxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (72)

Step A: 1-iodoethyl-p-nitrophenyl carbonate (73)

A mixture of 1-chloroethyl-p-nitrophenyl carbonate (0.5 g, 2 mmol) and NaI (0.6 g, 4 mmol) in dry acetone was stirred at 40 ° C for 3 hours. After filtration, the filtrate was concentrated under reduced pressure to afford 480 mg (72%) of the title compound (73), which was used in the next reaction without further purification.

Step B: α-Propanoyloxyethyl p-nitrophenyl carbonate (74)

A mixture of 1-iodoethyl p-nitrophenyl carbonate (73) (0.51 g, 1.5 mmol) and silver propionate (0.54 g, 3 mmol) in toluene (20 mL) was stirred at 50 ° C for 24 h. The reaction mixture was filtered to remove solids and the filtrate concentrated under reduced pressure. Chromatography of the resulting residue on silica gel (20% CH ₂ Cl ₂ / hexane and then 40% CH ₂ Cl ₂ / hexane) gave 0.39 g (92%) of the title compound (74). ¹ H-NMR _(CDCl3, 400 MHz): 1.16 (t, J = 7.6 Hz, 3H), 1.61 (d, J = 5.6 Hz, 3H), 2.41 (q, J = 7.6 Hz, 2H), 6.84 (q, 1H, J = 5.6 Hz), 7.39 (d, J = 9.2 Hz, 2H), 8.28 (d, J = 9.2 Hz, 2H).

Step C: 1 - {[(α-Propanoyloxyethoxycarbonyl) aminomethyl} -1-cyclohexaneacetic acid (72)

To a mixture of gabapentin (160 mg, 2.76 mmol) and triethylamine (0.77 mL, 5.5 mmol) in dichloromethane (30 mL) was added trimethylchlorosilane (0.71 mL, 5.5 mmol) and the resulting mixture was stirred until a clear solution was formed. To the above solution was added a solution of α-propanoyloxyethyl p-nitrophenyl carbonate (74) (0.39 g, 1.4 mmol) in dichloromethane (10 ml). After stirring for 30 minutes, the reaction mixture was washed with 10% citric acid (20 ml) and the organic phase was separated. The aqueous phase was further extracted with ether (3 x 10 ml) and the combined organic extracts were dried over MgSO ₄ . After removing the solvent under reduced pressure, the residue was purified by preparative reverse phase HPLC (acetonitrile, water, 1% formic acid) to afford 190 mg (44%) of the title compound (72). ¹ H-NMR (CD ₃ OD, 400 MHz): 1.09 (t, J = 7.6 Hz, 3H), 1.36-1.54 (m, 10H), 1.44 (d, J = 5.6Hz, 3H), 2.28 (s, 2H), 2.31 (q, J = 7.6Hz, 2H), 3.22 (s, 2H), 6.67 (q, J = 5.6 Hz, 1H). MS (ESI) m / z 316.25 (M + H) ⁺ .

(COMPARISON) EXAMPLE 12

1 - {(α-butanoyloxyethoxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (75)

Step A: α-Butanoyloxyethyl p-nitrophenyl carbonate (76)

A mixture of 1-iodoethyl p-nitrophenyl carbonate (73) (1.5 g, 4.5 mmol) and silver butyrate (1.3 g, 6.7 mmol) in toluene (40 mL) was heated at 90 ° C for 24 h stirred in an oil bath. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Chromatography of the resulting residue on silica gel (20% CH ₂ Cl ₂ / hexane and then 40% CH ₂ Cl ₂ / hexane) gave 0.46 g (36%) of the title compound (76). ¹ H-NMR _(CDCl3, 400 MHz): 0.95 (t, J = 7.6 Hz, 3H), 1.61 (d, J = 5.6 Hz, 3H), 1.67 (m, 2H), 2.41 (t, J = 7.6Hz, 2H), 6.84 (q, 1H, J = 5.6Hz), 7.39 (d, J = 9.2Hz, 2H) , 8.28 (d, J = 9.2 Hz, 2H). MS (ESI) m / z 298.28 (M + H) ⁺ .

Step B: 1 - {[(α-Butanoyloxyethoxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (75)

To a mixture containing gabapentin (530 mg, 3.1 mmol) and triethylamine (0.89 mL, 6.4 mmol) in dichloromethane (30 mL) was added trimethylchlorosilane (0.83 mL, 6.4 mmol) and the resulting mixture was stirred until a clear solution was formed. To this solution was added a solution of α-butanoyloxyethyl p-nitrophenyl carbonate (76) (0.46 g, 1.6 mmol) in dichloromethane (10 ml) and the resulting mixture was stirred for 30 min. The reaction mixture was washed with 10% citric acid (20 ml) and the organic phase was separated. The aqueous phase was further extracted with ether (3 x 10 ml) and the combined organic phases were dried over MgSO ₄ and then concentrated in vacuo. The resulting residue was purified by preparative reverse phase HPLC (acetonitrile, water, 1% formic acid) to afford 70 mg (21%) of the title compound (75). ¹ H-NMR (CD ₃ OD, 400 MHz): 0.95 (t, J = 7.6 Hz, 3H), 1.32-1.58 (m, 10H), 1.42 (d, J = 5.6 Hz, 3H), 1.67 (m, 2H), 2.24 (s, 2H), 2.30 (t, J = 7.6 Hz, 2H), 3.24 (s, 2H) , 6.74 (q, J = 5.6 Hz, 1H). MS (ESI) m / z 330.28 (M + H) ⁺ .

The acid form was quantitatively converted to the corresponding sodium salt by dissolving in water (5 ml), adding an equimolar amount of 0.5N NaHCO ₃ solution, followed by lyophilization.

EXAMPLE 13

1 - {[(α-isobutanoyloxyethoxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (77)

Following the procedure of Example 12 and replacing the silver butyrate with silver isobutyrate afforded 70 mg (21%) of the title compound (77). ¹ H-NMR (CD ₃ OD, 400 MHz): 1.12 (d, J = 7.2 Hz, 3H), 1.14 (d, J = 7.2 Hz, 3H), 1.32-1.58 (m, 10H), 1.44 (d, J = 5.6Hz, 3H), 2.28 (s, 2H), 2.56 (m, 1H), 3.25 (m, 2H), 6.73 (q, J = 5.6 Hz, 1H). MS (ESI) m / z 330.30 (M + H) ⁺ .

The acid form was quantitatively converted to the corresponding sodium salt by dissolving in water (5 ml), adding an equimolar amount of 0.5N NaHCO ₃ solution, followed by lyophilization.

(COMPARATIVE) EXAMPLE 14

1 - {[(α-Pivaloxyethoxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (78)

Following the procedure of Example 12 and replacing the silver butyrate with silver pivalate afforded 80 mg (36%) of the title compound (78). ¹ H-NMR _(CDCl3, 400 MHz): 1.13 (s, 9H), 1.32 to 1.58 (m, 10H), 1.41 (d, J = 5.6 Hz, 3H), 2.27 (s, 2H), 3.25 (m, 2H), 5.41 (t, 1H), 6.73 (q, J = 5.6Hz, 1H). MS (ESI) m / z 344.20 (M + H) ⁺

The acid form was quantitatively converted to the corresponding sodium salt by dissolving in water (5 ml), adding an equimolar amount of 0.5N NaHCO ₃ , followed by lyophilization.

(COMPARISON) EXAMPLE 15

1 - {[(α-acetoxyisobutoxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (79)

Following the procedure of Example 2 and replacing the chloroformic acid 1-chloroethyl ester with 1-chloro-2-methylpropyl chloroformate afforded 212 mg (38%) of the title compound (79). ¹ H-NMR (CD ₃ OD, 400 MHz): 0.99 (m, 6H), 1.32-1.58 (m, 10H), 1.88 (m, 1H), 2.08 (s, 3H), 2.38 (s, 2H), 3.25 (s, 2H), 6.52 (d, J = 4.4 Hz, H); MS (ESI) m / z 330.30 (M + H) ⁺ .

(COMPARISON) EXAMPLE 16

1 - {[(α-Propanoyloxyisobutoxy) carbonyl] aminomethyl} -1-cyclohexanessenic acid (80)

Following the procedure of Example 11 and replacing the 1-chloroethyl p-nitrophenyl carbonate with 1-chloro-2-methylpropyl p-nitrophenyl carbonate afforded 190 mg (44%) of the title compound (80). ¹ H-NMR (CD ₃ OD, 400 MHz): 0.90 (d, J = 6.6 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H), 0.98 (t , J = 7.6 Hz, 3H), 1.32-1.58 (m, 10H), 1.83 (m, 1H), 2.18 (s, 2H), 2.28 (q, J = 7.6 Hz, 2H), 3.25 (s, 2H), 6.52 (d, J = 4.4 Hz, 1H). MS (ESI) m / z 344.34 (M + H) ⁺ .

(COMPARATIVE) EXAMPLE 17

1 - {[(α-butanoyloxyisobutoxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (81)

Following the procedure of Example 2 and replacing the chloroformic acid 1-chloroethyl ester and the mercury acetate with 1-chloro-2-methylpropyl chloroformate and mercuric butyrate afforded 95 mg (36%) of the title compound (81). ¹ H-NMR (CD ₃ OD, 400 MHz): 1.12 (t, J = 7.6 Hz, 3H), 1.13 (d, J = 6.6 Hz, 3H), 1.14 (i.e. , J = 6.6 Hz, 3H), 1.32-1.58 (m, 10H), 1.87 (m, 2H), 2.22 (m, 1H), 2.42 (s, 2H) , 2.46 (t, J = 7.6 Hz, 2H), 3.44 (m, 2H), 6.78 (d, J = 4.8 Hz, 1H). MS (ESI) m / z 358.30 (M + H) ⁺ .

(COMPARISON) EXAMPLE 18

1 - {[(α-isobutanoyloxyisobutoxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (82)

Following the procedure of Example 2 and replacing the chloroformic acid 1-chloroethyl ester or mercury acetate with 1-chloro-2-methylpropyl chloroformate and mercury isobutyrate afforded 95 mg (36%) of the title compound (82). ¹ H-NMR (CD ₃ OD, 400 MHz): 0.95 (d, J = 7.2 Hz, 3H), 0.97 (d, J = 7.2 Hz, 3H), 1.05 (i.e. , J = 6.6 Hz, 3H), 1.06 (d, J = 6.6 Hz, 3H), 1.32-1.58 (m, 10H), 1.98 (m, 1H), 2 , 24 (s, 2H), 2.45 (m, 1H), 3.24 (m, 2H), 6.42 (d, J = 4.8 Hz, 1H). MS (ESI) m / z 358.27 (M + H) ⁺ .

(COMPARISON) EXAMPLE 19

1 - {[(α-Pivaloxyisobutoxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (83)

Following the procedure of Example 12 and replacing the 1-chloroethyl p-nitrophenyl carbonate or silver butyrate with 1-chloro-2-methylpropyl p-nitrophenyl carbonate and silver pivalate afforded 10 mg (9%) of the title compound (83). ¹ H-NMR (CD ₃ OD, 400 MHz): 0.98 (d, J = 6.6 Hz, 3H), 0.99 (d, J = 6.6 Hz, 3H), 1.19 (s , 9H), 1.32-1.58 (m, 10H), 2.08 (m, 1H), 2.28 (s, 2H), 3.21 (m, 2H), 6.49 (d, 1H); MS (ESI) m / z 372.31 (M + H) ⁺ .

(COMPARISON) EXAMPLE 20

1 - {[(α-benzoyloxyisobutoxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (84)

Following the procedure of Example 11 and replacing the 1-chloroethyl-1-p-nitrophenyl carbonate or silver propionate with 1-chloro-2-methylpropyl p-nitrophenyl carbonate and silver benzoate afforded 109 mg (40%) of the title compound (84). ¹ H-NMR (CD ₃ OD, 400 MHz): 1.18 (d, J = 7.2 Hz, 6H), 1.32-1.58 (m, 10H), 2.42 (m, 1H) , 2.28 (s, 2H), 3.45 (s, 2H), 6.99 (d, J = 4.8Hz, 1H), 7.76 (m, 2H), 7.92 (m, 1H), 8.26 (m, 2H). MS (ESI) m / z 392.22 (M + H) ⁺ .

(COMPARISON) EXAMPLE 21

1 - {[(α-acetoxyisopropoxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (85)

Step A: Isopropenyl p-nitrophenyl carbonate (86)

To a mixture of p-nitrophenol (5.76 g, 41.5 mmol) and isopropenyl chloroformate (5 g, 41.5 mmol) in dichloromethane (200 mL) at 0 ° C was added a solution of pyridine (3.4 mL, 42 mmol) in dichloromethane (50 ml). The resulting mixture was stirred at 0 ° C for 30 minutes and then at room temperature for 1 hour. After removing the solvent under reduced pressure, the residue was dissolved in ether and washed with water, 10% citric acid and water again. The ether phase was dried over Na ₂ SO ₄ and evaporated under reduced pressure to give 8.7 g (94%) of the title compound (86) as a cream solid. ¹ H-NMR _(CDCl3, 400 MHz): 2.05 (s, 3H), 4.81 (m, 1H), 4.95 (d, J = 2 Hz, 1H), 7.42 (d, J = 9.2 Hz, 2H), 8.28 (d, J = 9.2 Hz, 2H).

Step B: 2-Chloroisopropyl p-nitrophenyl carbonate (87)

Isopropenyl p-nitrophenyl carbonate (86) (8.7 g, 39 mmol) was dissolved in 4 M hydrogen chloride / dioxane in a sealed vessel. The mixture was stirred at room temperature for 16 hours. Removal of the solvent under reduced pressure gave 10 g (100%) of the title compound (87), which was used in the next reaction without further purification. ¹ H-NMR _(CDCl3, 400 MHz): 2.10 (s, 6H), 7.42 (d, 2H, J = 9.2 Hz), 8.28 (d, J = 9.2 Hz, 2H).

Step C: α-Acetoxy-isopropyl-p-nitrophenyl carbonate (88)

A mixture of 2-chloroisopropyl p-nitrophenyl carbonate (87) (0.5g, 1.93mmol) and mercuric acetate (1.0g, 3.13mmol) in dichloromethane (20ml) was stirred at room temperature for 24 hours. The reaction mixture was filtered to remove solid and the filtrate concentrated under reduced pressure. Chromatography of the resulting residue on silica gel (20% CH ₂ Cl ₂ / hexane and then 40% CH ₂ CL ₂ / hexane) provided 227 mg (50%) of the title compound (88). ¹ H-NMR _(CDCl3, 400 MHz): 1.90 (s, 6H), 2.07 (s, 3H), 7.28 (d, 2H, J = 9.2 Hz), 8.28 ( d, J = 9.2 Hz, 2H).

Step D: 1 - {[(α-Acetoxyisopropoxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (85)

To a mixture containing gabapentin (257 mg, 1.5 mmol) and triethylamine (0.46 mL, 3.3 mmol) in dichloromethane (30 mL) was added trimethylchlorosilane (0.38 mL, 3 mmol) and the mixture was stirred until it was clear. A solution containing α-acetoxyisopropyl p-nitrophenyl carbonate (88) (0.23 g, 0.8 mmol) in dichloromethane (10 ml) was added and stirred for 30 minutes. The reaction mixture was washed with brine (10 ml) and the organic phase was separated. The aqueous phase was further extracted with ether (3 x 10 mL) and the combined organic extracts were dried over MgSO ₄ and then concentrated in vacuo. Chromatography of the resulting residue on silica gel (hexane: Ethyl acetate (4: 1)) gave 40 mg (16%) of the title compound (85). ¹ H-NMR (CD ₃ OD, 400 MHz): 1.32-1.58 (m, 10H), 1.80 (s, 6H), 2.02 (s, 3H), 2.27 (s, 2H), 3.30 (s, 2H). MS (ESI) m / z 316,21 (M + H) ⁺ .

(COMPARISON) EXAMPLE 22

1 - {[(α-butanoyloxyisopropoxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (89)

Following the procedure of Example 21 and replacing the mercury acetate with mercury butyrate afforded 5 mg (5%) of the title compound (89). ¹ H-NMR (CD ₃ OD, 400 MHz): 0.99 (t, J = 7.6 Hz, 3H), 1.32-1.58 (m, 10H), 1.60 (m, 2H) , 1.85 (s, 6H), 2.22 (t, J = 7.6 Hz, 2H), 2.27 (s, 2H), 3.20 (s, 2H). MS (ESI) m / z 344.24 (M + H) ⁺ , 366.30 (M + Na) ⁺ .

(COMPARATIVE) EXAMPLE 23

1 - {[(α-isobutanoyloxyisopropoxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (90)

Following the procedure of Example 21 and replacing the mercury acetate with mercury isobutyrate afforded 109 mg (43%) of the title compound (90). ¹ H-NMR (CD ₃ OD, 400 MHz): 1.19 (d, J = 7.2 Hz, 6H), 1.32-1.58 (m, 10H), 1.82 (s, 6H) , 2.38 (s, 2H), 3.25 (s, 2H). MS (ESI) 344.22 (M + H) ⁺ , 366.24 (M + Na) +.

(COMPARATIVE) EXAMPLE 24

1 - {[(α-benzoyloxyisopropoxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (91)

Following the procedure of Example 21 and replacing the mercury acetate with mercuric benzoate provided 170 mg (58%) of the title compound (91). ¹ H-NMR _(CDCl3, 400 MHz): 1.32 to 1.58 (m, 10H), 1.95 (s, 6H), 2.30 (s, 2H), 3.20 (d, J = 6.8 Hz, 2H), 5.41 (t, J = 6.8 Hz, 1H), 7.40 (m, 2H), 7.52 (m, 1H), 7.98 (m, 2H ). MS (ESI) m / z 400.29 (M + Na) ⁺ .

(COMPARATIVE) EXAMPLE 25

1 - {[(α-nicotinoyloxyisobutoxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (92)

Step A: 1 - {[(α-Chloroisobutoxy) carbonyl] aminomethyl-1-cyclohexanoacetic acid (93)

To a mixture containing gabapentin (1.71 g, 10 mmol) and triethylamine (3.06 mL, 22 mmol) in dichloromethane (150 mL) was added trimethylchlorosilane (1.4 mL, 11 mmol) and the resulting mixture became stirred until it was clear (about 20 min). A solution containing chloroformic acid 1-chloro-2-methylpropyl ester (1.27 mL, 11 mmol) in dichloromethane (10 mL) was then added at 0 ° C and stirred at room temperature for 60 min. The reaction mixture was washed with 10% citric acid (30 ml) and the organic phase separated. The aqueous phase was further extracted with ether (3 x 20 ml) and the combined organic phases were dried over MgSO ₄ and then concentrated in vacuo. Chromatography of the residue on silica gel eluting with hexane: ethyl acetate (1: 4) gave 2.37 g (77%) of the title compound. ¹ H-NMR _(CDCl3, 400 MHz): δ 1.04 (d, J = 6.4 Hz, 3H), 1.06 (d, J = 6.4 Hz, 3H), 1.36 to 1 , 53 (m, 10H), 2.15 (m, 1H), 2.34 (s, 2H), 3.24 (m, 2H), 5.39 (t, 1H), 6.32 (d, J = 5.6 Hz, 1H). MS (ESI) m / z 306.34 (M + H ⁺ ).

Step B: 1-1 {[(α-Nicotinoyloxyisobutoxy) carbonylaminomethyl} -1-cyclohexaneacetic acid (92)

A mixture of (93) (268 mg, 0.88 mmol), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) (158 μl, 1.01 mmol) and nicotinic acid (637 mg, 5 , 2 mmol) in acetone was stirred at room temperature for 48 h. After filtration, the filtrate was concentrated in vacuo and the resulting residue was purified by preparative reverse phase HPLC to afford 50 mg (14%) of the title compound. ¹ H-NMR (CD ₃ OD, 400 MHz): δ 1.07 (d, J = 6.8 Hz, 3H), 1.09 (d, J = 6.8 Hz, 3H), 1.32 1.58 (m, 10H), 2.19 (m, 1H), 2.26 (s, 2H), 3.23 (m, 2H), 6.78 (d, J = 4.8 Hz, 1H ), 7.58 (m, 1H), 8.39 (d, J = 6.4Hz, 1H), 8.76 (d, J = 4.4Hz, 1H), 9.10 (s, 1H ). MS (ESI) m / z 393.42 (M + H ⁺ ).

(COMPARATIVE) EXAMPLE 26

1 - {[(α-2,2-Diethoxypropanoyloxyisobutoxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (94)

Step A: 1 - {[(α-Chloroisobutoxy) carbonyl] aminomethyl} -1-cyclohexanacetic acid benzyl ester (95)

To a solution of (93) (1.02 g, 3.34 mmol) in dichloromethane was added 1,3-dicyclohexylcarbodiimide (758 mg, 3.67 mmol). After stirring at room temperature for 30 minutes, benzyl alcohol (380 μl, 3.67 mmol) and 4- (dimethylamino) pyridine (catalytic amount) were added. The resulting mixture was stirred at room temperature for 16 hours. After filtration, the filtrate was washed with 10% citric acid, dried over Na ₂ SO ₄ and concentrated. Chromatography of the residue on silica gel eluting with 10% ethyl acetate / hexane gave 820 mg (62%) of the title compound. ¹ H-NMR _(CDCl3, 400 MHz): δ 1.03 (d, J = 6.4 Hz, 3H), 1.05 (d, J = 6.4 Hz, 3H), 1.36 to 1 , 53 (m, 10H), 2.13 (m, 1H), 2.35 (s, 2H), 3.22 (m, 2H), 5.11 (s, 2H), 5.49 (t, 1H), 6.32 (d, J = 4.8Hz, 1H), 7.34 (m, 5H). MS (ESI) m / z 396.24 (M + H ⁺ ).

Step B: Cesium 2,2-diethoxypropionate (96)

While stirring, 1 ml of concentrated sulfuric acid was added to a solution of 14 ml (0.2 mol) of pyruvic acid and 80 ml of triethyl orthoformate at 10 ° C. The resulting mixture was stirred at 5-10 ° C for 1 h and then diluted with 200 ml of dichloromethane. The organic solution was washed successively with water (3 × 80 ml) and saturated sodium chloride solution (80 ml), and then dried over anhydrous sodium sulfate. The mixture was filtered and then concentrated to give a quantitative yield of 2,2-diethoxypropionic acid as an oil. ¹ H-NMR _(CDCl3, 400 MHz): δ 1.30 (t, 6H), 1.61 (s, 3H), 3.57 (q, 4H), 8.62 (s, 1H). The acid form was quantitatively converted to its cesium salt by dissolving the acid in water (25 ml) followed by treatment with an equimolar amount of cesium carbonate and then lyophilization. ¹ H-NMR (D ₂ O, 400 MHz): δ 0.98 (t, 6H), 1.28 (s, 3H), 3.22 (q, 2H), 3.47 (q, 2H).

Step C: 1 - {[(α-2,2-Diethoxypropanoyloxyisobutoxy) carbonyl) aminomethyl} -1-cyclohexaneacetic acid benzyl ester (97)

A mixture of (95) (200 mg, 0.51 mmol) and sodium iodide (114 mg, 0.76 mmol) in acetone was stirred for 1 h at room temperature. Cesium 2,2-diethoxypropionate (96) (300 mg, 1.02 mmol) and DMF (20 mL) were added and the resulting mixture was stirred at 40 ° C for 18 h. After filtration, the filtrate was concentrated and the resulting residue was purified by flash chromatography on silica gel eluting with 10% ethyl acetate / hexane to afford 100 mg (37%) of the title compound. MS (ESI) m / z 522.34 (M + H ⁺ ).

Step D: 1 - {[(α-2,2-Diethoxypropanoyloxyisobutoxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (94)

A mixture of (97) (200 mg, 0.38 mmol) and 5% Pd-C (catalytic amount) was stirred under hydrogen at room temperature for 16 h. After filtration, the filtrate was concentrated and the resulting residue was purified by preparative reverse phase HPLC to afford 98 mg (60%) of the title compound. ¹ H-NMR _(CDCl3, 400 MHz): δ 0.97 (d, J = 6.8 Hz, 6H), 1.19 (t, J = 6.4 Hz, 3H), 1.21 (t , J = 6.4 Hz, 3H), 1.32-1.58 (m, 10H), 1.51 (s, 3H), 2.06 (m, 1H), 2.30 (s, 2H) , 3.23 (m, 2H), 3.46 (m, 2H), 3.56 (m, 2H), 5.30 (t, 1H, NH), 6.59 (d, J = 4.8 Hz, 1H). MS (ESI) m / z 432.24 (M + H ⁺ ).

(COMPARATIVE) EXAMPLE 27

1 - {[(α- (2-amino-2-methylpropanoyloxyisobutoxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (98)

Following the procedure of Example 26 and replacing the 2,2-diethoxypropionic acid with 2-amino-2-methylpropionic acid afforded the title compound. ¹ H-NMR _(CDCl3, 400 MHz): δ 0.97 (d, J = 6.8 Hz, 6H), 1.44 (s, 3H), 1.45 (s, 3H), 1.32 -1.58 (m, 10H), 2.05 (m, 1H), 2.30 (s, 2H), 3.23 (m, 2H), 5.50 (t, 1H, NH), 6, 58 (d, J = 4.8 Hz, 1H). MS (ESI) m / z 373.48 (M + H ⁺ ).

(COMPARATIVE) EXAMPLE 28

1 - {[(α-isobutanoyloxybutoxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (99)

Step A: 2-Isopropyl-1,3-dithiane (100)

To a mixture of isobutyraldehyde (9.1 mL, 100 mmol) and 1,3-propanedithiol (10 mL, 100 mmol) in dichloromethane at 0 ° C was added boron trifluoride diethyl etherate (6.4 mL, 50 mmol). The resulting mixture was stirred at 0 ° C for 30 minutes and at room temperature for 30 minutes. The reaction mixture was washed with brine, 5% NaHCO _3, and brine again. The organic phase was separated, dried over Na ₂ SO ₄ and concentrated to give 16 g (100%) of the title compound as a yellow liquid. This was fed to the next step without further purification. ¹ H-NMR _(CDCl3, 400 MHz): δ 1.057 (d, J = 7.2 Hz, 3H), 1.059 (d, J = 7.2 Hz, 3H), 1.80 (m, 1H), 1.97-2.08 (m, 2H), 2.82 (m, 4H), 4.00 (d, J = 5.2Hz, 1H).

Step B: 2-Isopropyl-2- (α-hydroxybutyl) -1,3-dithiane (101)

To a solution of (100) (4 g, 24.7 mmol) in anhydrous tetrahydrofuran (50 mL) was added dropwise n-butyllithium (1.6 M in hexane, 18.5 mL, 29.6 mmol) at -20 ° C. added. With stirring, the mixture was allowed to warm to room temperature over 4 hours and then cooled again to -20 ° C. To this solution was added slowly a solution of n-butyraldehyde (2.7 mL, 29.6 mmol) in anhydrous tetrahydrofuran (10 mL). The resulting mixture was stirred for 16 h between -20 ° C and room temperature. The reaction was quenched with saturated ammonium chloride solution and the mixture extracted with ethyl acetate. The organic phase was separated and dried over Na ₂ SO ₄ . After removing the solvent under reduced pressure, flash column chromatography of the residue on silica gel eluting with 5% ethyl acetate / hexane afforded 5 g (85%) of the title compound as a yellow oil. ¹ H-NMR _(CDCl3, 400 MHz): δ 0.96 (t, J = 7.2 Hz, 3H), 1.11 (d, J = 6.8 Hz, 3H), 1.17 (d , J = 6.8 Hz, 3H), 1.42-1.52 (m, 2H), 1.76 (m, 1H), 1.87-1.95 (m, 2H), 2.04 ( m, 2H), 2.62 (m, 4H), 2.94 (m, 2H), 4.03 (d, J = 5.2Hz, 1H).

Step C: 4-hydroxy-2-methylheptan-3-one (102)

To a solution of (101) (5.0 g, 21.4 mmol) in acetonitrile (270 mL) was added a solution of Hg (ClO ₄ ) ₂ in methanol (30 mL) with vigorous stirring. The resulting mixture was stirred for 2 hours at room temperature. After filtration, the filtrate was carefully concentrated under reduced pressure without heating. Purification of the residue using flash column chromatography (10% ethyl acetate / hexane) on silica gel afforded 2.8 g (91%) of the title compound as a colorless liquid. ¹ H-NMR _(CDCl3, 400 MHz): δ 0.91 (t, J = 7.2 Hz, 3H), 1.09 (d, J = 7.2 Hz, 3H), 1.10 (d , J = 7.2 Hz, 3H), 1.35-1.46 (m, 4H), 1.75 (m, 1H), 2.80 (m, 1H), 3.45 (d, J = 5.2 Hz, 1H), 4.29 (m, 1H).

Step D: 2-Methylheptan-3-one-4-p-nitrophenyl carbonate (103)

To a mixture of (102) (1.1 g, 7.6 mmol) and p-nitraphenyl chloroformate (1.84 g, 9.2 mmol) in anhydrous dichloromethane at 0 ° C was slowly added a solution of 4-dimethylaminopyridine ( 1.12 g, 9.2 mmol) in dichloromethane. After stirring for 1 hour at 0 ° C and 4 hours of stirring. at room temperature, the reaction was quenched with 10% citric acid. The organic phase was separated, dried over Na ₂ SO ₄ and concentrated in vacuo. Flash column chromatography of the residue eluting with 30% dichloromethane / hexane afforded 2 g (85%) title compound as a cream colored solid ¹ H-NMR _(CDCl3, 400 MHz): δ 0.99 (t, J = 7.6 Hz, 3H), 1.12 (d, J = 6.8Hz, 3H), 1.18 (d, J = 6.8Hz, 3H), 1.51 (m, 2H), 1.84 (m, 2H), 2.82 (m, 1H), 5.17 (m, 1H), 7.42 (d, J = 6.8 Hz, 2H), 8.25 (d, J = 6.8 Hz, 2H).

Step E: 1 - {[(α-Isobutanoylbutoxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (104)

To a mixture containing gabapentin (820 mg, 4.8 mmol) and triethylamine (1.35 mL, 9.6 mmol) in dichloromethane (20 mL) was added trimethylchlorosilane (1.22 mL, 9.6 mmol) and the resulting mixture was stirred for 20 minutes. To this solution was added (103) (1 g, 3.2 mmol) in dichloromethane (10 ml) and the resulting mixture was stirred for 60 min. The reaction mixture was washed with 10% citric acid (20 ml) and the organic phase separated. The aqueous phase was further extracted with ether (3 x 10 mL) and the combined organic extracts were dried over MgSO ₄ and then concentrated in vacuo. Chromatography of the residue on silica gel eluting with hexane: ethyl acetate (4: 1) to remove p-nitrophenol then further eluting with hexane: ethyl acetate (1: 4) gave 780 mg (72%). Title compound. ¹ H-NMR _(CDCl3, 400 MHz): δ 0.91 (t, J = 7.2 Hz, 3H), 1.04 (d, J = 6.8 Hz, 3H), 1.12 (d , J = 6.8 Hz, 3H), 1.36-1.53 (m, 12H), 1.74 (m, 2H), 2.33 (s, 2H), 2.78 (m, 1H) , 3.22 (m, 2H), 5.11 (m, 1H), 5.48 (t, 1H, NH). MS (ESI) m / z 342.24 (M + H ⁺ ).

Step F: 1 - {[(α-Isobutanoyloxybutoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid (99)

To a solution of (104) (780 mg, 2.3 mmol) in dichloromethane (20 mL) was added m-chloroperaxybenzoic acid (1.03 g, 4.6 mmol) and NaHCO ₃ (386 mg, 4.6 mmol).

After stirring for 16 h at room temperature, another charge of m-chloroperoxybenzoic acid (791 mg, 4.6 mmol) and NaHCO ₃ (386 mg, 4.6 mmol) were added. The resulting mixture was stirred for a further 8 h and then treated with 10% citric acid. After filtration, the organic phase was separated, dried over Na ₂ SO ₄ and concentrated. The residue was purified by preparative reverse phase HPLC to afford 79 mg (11%) of the title compound. ¹ H-NMR _(CDCl3, 400 MHz): δ 0.94 (t, J = 7.2 Hz, 3H), 1.153 (d, J = 7.2 Hz, 3H), 1.150 (d, J = 7 , 2Hz, 3H), 1.32-1.58 (m, 12H), 1.74 (m, 2H), 2.28 (s, 2H), 2.56 (m, 1H), 3.23 (m, 2H), 5.27 (t, J = 6.8Hz, 1H, NH), 6.71 (t, J = 5.6Hz, 1H). MS (ESI) m / z 358.30 (M + H ⁺ ).

The above acid was quantitatively converted to the corresponding sodium salt by dissolving the acid in water (5 ml) followed by addition of an equimolar amount of 0.5N NaHCO ₃ solution and lyophilization.

(COMPARATIVE) EXAMPLE 29

1 - {[(α-isobutanoyloxyisobutoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid methyl ester (105)

Step A: 1 - {[(α-Chloroisobutoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid methyl ester (106)

A mixture of (93) (1.0 g, 3.3 mmol), benzene (90 ml) and methanol (10 ml) was cooled to 0 ° C. Trimethylsilyldiazomethane was added slowly at 0 ° C until the yellow color persisted. The mixture was stirred at 0 ° C for 30 min until the reaction was complete (monitored by TLC). After removing the solvent under reduced pressure, chromatography of the resulting residue on silica gel eluting with 10% ethyl acetate / hexane gave 760 mg (72%) of the title compound. MS (ESI) m / z 320.24 (M + H ⁺ ).

Step B: 1 - {[(α-Isobutanoyloxyisobutoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid methyl ester (105)

A mixture of (106) (760 mg, 2.38 mmol), silver carbonate (394 mg, 1.4 mmol) and isobutyric acid (442 μL, 4.76 mmol) in chloroform was stirred at room temperature for 24 h. Another batch of silver carbonate (394 mg, 1.4 mmol) and isobutyric acid (442 μl, 4.76 mmol) was added and the resulting mixture was stirred for a further 24 h. After filtration, the filtrate was concentrated and the resulting residue was purified by flash column chromatography on silica gel eluting with 10% ethyl acetate / hexane to afford 560 mg (63%) of the title compound. ¹ H-NMR _(CDCl3, 400 MHz): δ 0.94 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H), 1.15 (d , J = 7.2 Hz, 3H), 1.17 (d, J = 7.2 Hz, 3H), 1.32-1.58 (m, 10H), 2.01 (m, 1H), 2 , 19 (s, 2H), 2.55 (m, 1H), 3.18 (m, 2H), 3.67 (s, 3H), 5.33 (t, 1H), 6.56 (d, J = 4.8 Hz, 1H). MS (ESI) m / z 372.38 (M + H ⁺ ).

(COMPARISON) EXAMPLE 30

1 - {[(α-Benzoyloxyisobutoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid methyl ester (107)

A mixture of 1 - {[(α-benzoyloxyisobutoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid (84) (150 mg, 0.38 mmol), benzene (18 mL) and methanol (2 mL) was cooled to 0 ° C , Trimethylsilyldiazomethane was added slowly at 0 ° C until the yellow color persisted. The mixture was stirred at 0 ° C for 30 min until the reaction was complete (monitored by TLC). After removing the solvent under reduced pressure, chromatography of the residue on silica gel eluting with 5% ethyl acetate / hexane gave 98 mg (64%) of the title compound. ¹ H-NMR _(CDCl3, 400 MHz): δ 1.02 (d, J = 6.4 Hz, 3H), 1.03 (d, J = 6.4 Hz, 3H), 1.32 to 1 , 52 (m, 10H), 2.14 (m, 1H), 2.27 (s, 2H), 3.17 (m, 2H), 3.62 (s, 3H), 5.40 (t, 1H), 6.81 (d, J = 4.8Hz, 1H), 7.40 (m, 2H), 7.54 (m, 1H), 8.12 (m, 2H). MS (ESI) m / z 406.29 (M + H ⁺ ).

(COMPARISON) EXAMPLE 31

1 - {[N - [(α-isobutanoyloxyethoxy) carbonyl] -4-bromophenylalaninyl] aminomethyl} -1-cyclohexanoacetic acid (108)

Step A: 1 - {(4-Bromophenylalaninyl) aminomethyl} -1-cyclohexaneacetic acid (109)

To a 40 ml vial was added N-Boc-4-bromophenylalanine (1.72 g, 5 mmol), dicyclohexylcarbodiimide (1.24 g, 6 mmol), N-hydroxysuccinimide (0.7 g, 6 mmol) and acetonitrile (20 ml ) was added. The reaction mixture was shaken for 4 h at 25 ° C. The precipitated dicyclohexylurea was removed by filtration. To the filtrate was added an aqueous solution (30 ml) of gabapentin hydrochloride (1.04 g, 6 mmol) and sodium hydroxide (0.4 g, 10 mmol). The reaction mixture was stirred for 16 h at 22 to 25 ° C. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with 0.5 M aqueous citric acid (2 x 100 mL) and water (2 x 100 mL). The organic phase was separated, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue was dissolved in trifluoroacetic acid (40 ml) and allowed to stand for 2 h at 22 to 25 ° C. The solvent was removed under reduced pressure. The residue was dissolved in water (4 ml) and purified by preparative HPLC (Phenomenex 250 x 21.2 mm, 5 μm LUNA C18 column, 5% 100% water, then 0-60% acetonitrile in water over 20 minutes) with 0.05% TFA at 20 ml / min) through a 0.25 μm nylon membrane filter. The pure fractions were combined and the solvent was removed under reduced pressure to afford 1.7 g (70%) of the title compound (109) as a white solid. MS (ESI) m / z 397.02, 399.01 (M + H ⁺ ).

Step B: 1 - {[N-T [(α-isobutanoyloxyethoxy) carbonyl] -4-bromophenylalaninyl] aminomethyl} -1-cyclohexaneacetic acid (108)

With stirring, triethylamine (141 μl, 1.01 mmol) and trimethylchlorosilane (129 ml, 1.01 mmol) were added to a suspension of (109) (200 mg, 0.51 mmol) in dichloromethane at 0 ° C. The resulting mixture was stirred at 0 ° C for 15 min, then a solution of α-isobutanoyloxyethyl p-nitrophenyl carbonate (III) (144 mg, 0.51 mmol) in dichloromethane was added. The mixture was stirred for 7 h at room temperature (monitored by LC / MS) and then the reaction mixture was diluted with dichloromethane and acidified with citric acid. The organic phase was separated, washed with brine and dried over Na ₂ SO ₄ . After filtration and concentration, the crude product was purified by preparative LC / MS to afford 92 mg of the title compound. ¹ H-NMR (CD ₃ OD, 400 MHz): δ 1.10 (m, 6H), 1.46-1.25 (m, 13H), 2.20 (m, 2H), 2.48 (m , 1H), 2.84 (m, 1H), 3.06 (m, 1H), 3.17 (m, 1H), 4.36 (m, 1H), 6.67 (q, J = 5, 6 Hz, 1H), 7.17 (d, J = 2.0, 8.0 Hz, 2H), 7.42 (dd, J = 2.0, 8.0 Hz, 2H).

(COMPARATIVE) EXAMPLE 32

3 - {[(α-isobutanoyloxyethoxy) carbonyl) aminomethyl} -5-methylhexanoic acid (110)

Step A: α-Isobutanoyloxyethyl p-nitrophenyl carbonate (111)

A solution of 1-chloroethyl-p-nitrophenyl carbonate (57) (2.0 g, 8.14 mmol) and mercury isobutyrate (6.13 g, 16.29 mmol) in dichloromethane (10 mL) was heated at 45 ° C for 24 h touched. The reaction mixture was then cooled to room temperature and diluted with hexane to precipitate mercury salts. The precipitate was filtered through a celite pad and the filtrate was concentrated in vacuo to afford 2.5 g of crude product. Chromatography of the residue on silica gel eluting with a gradient from 10% dichloromethane / hexane to 20% dichloromethane / hexane provided 1.2 g (52%) of the title compound. ¹ H-NMR _(CDCl3, 400 MHz): δ 1.21 to 1.99 (m, 6H), 1.62 (d, J = 5.6 Hz, 3H), 2.61 (m, 1H) , 6.84 (q, J = 5.6 Hz, 1H), 7.41 (dt, J = 6.8, 2.4 Hz, 2H), 8.29 (dt, J = 6.8, 2 , 4 Hz, 2H).

Step B: 3 - {[(α-Isobutanoyloxyethoxy) carbonyl] aminomethyl} -5-methylhexanoic acid (110)

While stirring, triethylamine (0.26 mL, 1.88 mmol) and trimethylchlorosilane (0.24 mL, 1.88 mmol) was added. After stirring at 0 ° C for 15 minutes, a solution of α-isobutanoyloxyethyl p-nitrophenyl carbonate (III) (267 mg, 0.94 mmol) in dichloromethane (3 mL) was added. The resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was acidified with citric acid and extracted with dichloromethane. The combined organic extracts were washed with brine and dried over Na ₂ SO ₄ . After filtration and evaporation, the crude product was purified by silica gel chromatography first eluting with dichloromethane to remove nitrophenol, then with 30% ethyl acetate Dichloromethane to afford 130 mg (48%) of the title compound as a mixture of two diastereomers. ¹ H-NMR _(CDCl3, 400 MHz): δ 0.90 (m, 6H), 1.70 (m, 8H), 1.46 (d, J = 5.6 Hz, 3H), 1.66 (1H, m), 2.15 (m, 1H), 2.33 (m, 2H), 2.53 (m, 1H), 3.12 (m, 1H), 3.29 (m, 1H) , 5.08 (t, J = 6.0 Hz, 1H), 6.79 (m, 1H).

(COMPARATIVE) EXAMPLE 33

3 - {[(α-isobutanoyloxyisobutoxy) carbonyl] aminomethyl} -5-methylhexanoic acid (112)

Step A: 1-Chloro-2-methylpropyl-p-nitrophenyl carbonate (113)

An ice-cold reaction mixture containing p-nitrophenol (4.06 g, 29 mmol) and 1-chloro-2-methylpropyl chloroformate (5.0 g, 29 mmol) in dichloromethane (200 ml) was added a solution of pyridine ( 2.78 ml, 32 mmol) in dichloromethane (50 ml). The mixture was stirred at 0 ° C for 30 minutes and then at room temperature for 1 hour. After evaporation of the solvent under reduced pressure, the residue was dissolved in ether and washed with water, 10% citric acid and water again. The ether phase was separated, dried over Na ₂ SO ₄ and evaporated under reduced pressure to give 7.9 g (100%) of the title compound as a cream solid. ¹ H-NMR _(CDCl3, 400 MHz): δ 1.12 (d, J = 6.6 Hz, 3H), 1.13 (d, J = 6.6 Hz, 3H), 2.29 (m , 1H), 6.24 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 9.2 Hz, 2H), 8.28 (d, J = 9.2 Hz, 2H ).

Step B: α-Isobutanoyloxyisobutyl p-nitrophenyl carbonate (314)

Following the procedure to prepare (III) and replace (57) with (113) afforded the title compound in 15% yield with 70% recovery of the starting material. ¹ H-NMR _(CDCl3, 400 MHz): δ 1.07 (d, J = 6.8 Hz), 1.21 (m, 6H), 2.18 (m, 1H), 2.26 (m , 1H), 6.60 (d, J = 5.2 Hz, 1H), 7.42 (m, 2H), 8.28 (m, 2H).

Step C: 3 - {[(α-Isobutanoyloxyisobutoxy) carbonyl] aminomethyl} -5-methylhexanoic acid (112)

Following the procedure to prepare (110) and replace (111) with (114) afforded the title compound as a mixture of two diastereomers in 51% yield. ¹ H-NMR _(CDCl3, 400 MHz): δ 0.89 (m, 12H), 1.17 (m, 8H), 1.65 (m, 1H), 2.02 (m, 1H), 2 , 16 (m, 1H), 2.33 (m, 2H), 2.56 (m, 1H), 3.13 (m, 1H), 3.30 (m, 1H), 5.00 (m, 1H), 6.57-6.56 (m, 1H).

(COMPARATIVE) EXAMPLE 34

3 - {[(α-Benzoyloxyisobutoxy) carbonyl] aminomethyl} -5-methylhexanoic acid (115)

Step A: α-Benzoyloxyisobutyl p-nitrophenyl carbonate (116)

Following the procedure to prepare (III) and replace (57) with (113) and mercury isobutyrate with mercuric benzoate afforded the title compound in 11% yield with 50% recovery of the starting material. ¹ H-NMR _(CDCl3, 400 MHz): δ 1.15 (d, J = 3.2 Hz, 3H), 1.16 (d, J = 3.2 Hz, 3H), 2.30 (m , 1H), 6.87 (d, J = 4.4 Hz, 1H), 7.42 (dd, J = 7.2, 2.0 Hz, 2H), 7.48 (t, J = 7, 6 Hz, 2H), 7.62 (t, J = 7.6 Hz, 1H), 8.09 (dd, J = 8.0, 1.0 Hz, 2H), 8.27 (dd, J = 7.2, 2.0 Hz, 2H).

Step B: 3 - {[(α-Benzoyloxyisobutoxy) carbonyl] aminomethyl} -5-methylhexanoic acid (115)

Following the procedure to prepare (110) and replace (111) with (116) gave the title compound as a mixture of two diastereomers in 58% yield. ¹ H-NMR _(CDCl3, 400 MHz): δ 0.87 (m, 6H), 1.05 (m, 6H), 1.16 (m, 2H), 1.64 (m, 1H), 2 , 17 (m, 2H), 2.32 (m, 2H), 3.12 (m, 1H), 3.29 (m, 1H), 5.01 (br s, 1H), 6.82 (m , 1H), 7.44 (m, 2H), 7.57 (m, 1H), 8.05 (m, 2H).

(COMPARATIVE) EXAMPLE 35

1 - {[((5-methyl-2-oxo-1,3-dioxol-4-en-4-yl) methoxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (117)

Step A: Benzyl 2-diazo-3-oxobutyric acid (118)

To a solution of benzyl acetoacetate (5.0 g, 26.01 mmol) and 4-acetamidobenzenesulfonyl azide (6.25 g, 26.01 mmol) in acetonitrile (200 mL) was added dropwise at 0 ° C triethylamine (10.9 mL, 78 , 03 mmol) was added. The resulting mixture was stirred at 0 ° C for 30 minutes and at room temperature for 4 hours. After concentration under reduced pressure, the residue was triturated with 2: 1 ethyl ether / petroleum ether (3 × 100 ml). The combined organic extract was filtered through a silica pad covered Celite pad. Removal of the solvent under reduced pressure afforded 4.74 g of the title compound as cream-colored crystals. ¹ H-NMR _(CDCl3, 400 MHz): δ 2.49 (s, 3H), 5.27 (s, 2H), 7.38 (m, 5H).

Step B: Benzyl 2-hydroxy-3-oxobutyric acid (119)

A solution of the diazo compound (118) (4.74 g, 21.74 mmol) in THF (110 mL) and H ₂ O (50 mL) was treated with Rh ₂ (OAc) ₂ (77 mg, 0.17 mmol heated to reflux and allowed to cool to room temperature. The mixture was concentrated in vacuo and the aqueous residue was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to provide 4.5 g of crude product. ¹ H-NMR _(CDCl3, 400 MHz): δ 2.28 (s, 3H), 3.90 (s, 1H), 4.82 (s, 1H), 5.26 (m, 2H), 7 , 37 (m 5H).

Step C: 4-Benzyloxycarbonyl-5-methyl-2-oxo-1,3-dioxol-4-ene (120)

To a suspension of carbonyldiimidazole (6.88 g, 42.45 mmol) in THF (50 mL) at 0 ° C was added a solution of the alcohol (119) (4.50 g, 21.22 mmol) in dry THF (50 ml) was added. The resulting mixture was stirred at 0 ° C for 5 h and then at room temperature overnight. The mixture was concentrated in vacuo and the residue was partitioned between water and ethyl acetate / hexane. The organic phase was separated, washed with saturated NH ₄ Cl solution and brine and dried over Na ₂ SO ₄ . After filtration and concentration, the crude product was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane to afford 2.6 g of the title compound. ¹ H-NMR _(CDCl3, 400 MHz): δ 2.48 (s, 3H), 5.27 (s, 2H), 7.37 (br s, 5H).

Step D: 5-Methyl-2-oxo-1,3-dioxol-4-enyl-4-carboxylic acid (121)

To a solution of the compound (120) (2.6 g, 10.92 mmol) in 50 ml of ethanol was added 260 mg of Pd / C (5%), and the resulting mixture was stirred for 1 hour under a hydrogen atmosphere. Filtration and removal of the solvent under reduced pressure afforded 1.62 g of the title compound. ¹ H-NMR (CD ₃ OD, 400 MHz): δ 2.41 (s, 3H).

Step E: 4-hydroxymethyl-5-methyl-2-oxo-1,3-dioxol-4-ene (122)

To a solution of the acid (121) (1.62g, 11.10mmol) and anhydrous DMF (112μl) in dry dichloromethane (50ml) was added dropwise at 0 ° C oxalyl chloride (6.1ml of a 2M solution, 12.2 mmol) was added. After stirring at 0 ° C for 30 minutes and at room temperature for 1 hour, the solvent was removed under reduced pressure. The residue was dissolved in anhydrous dichloromethane (65 ml) and cooled to -78 ° C. To this solution was added dropwise over 10 minutes a solution of Bu ₄ NBH ₄ (3.14 g, 12.2 mmol, in 20 mL dichloromethane). After stirring at -78 ° C for 1 h, the mixture was quenched cautiously with 0.1 N HCl (30 mL) and allowed to warm to room temperature. The aqueous phase was separated and extracted with EtOAc (3 x 50 mL) and the combined organic extract was washed with brine and dried over Na ₂ SO ₄ . After removing the solvent under reduced pressure, column chromatography on silica gel eluting with 50% EtOAc in dichloromethane afforded 767 mg of the title compound. ¹ H-NMR (CD ₃ OD, 400 MHz): δ 2.09 (s, 3H), 4.34 (s, 2H).

Step F: 1 - {[((5-Methyl-2-oxo-1,3-dioxol-4-en-4-yl) methoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid benzyl ester (123)

A suspension of the alcohol (122) (767 mg, 5.9 mmol) and 1-isocyanatomethyl-1-cyclohexaneacetic acid benzyl ester (5.9 mmol) in toluene was refluxed overnight. After removing the Solvent under reduced pressure, the residue was purified by flash column chromatography eluting with 30% EtOAc in hexane to provide 510 mg of the title compound. ¹ H-NMR (CD ₃ OD, 400 MHz): δ 1.58-1.30 (m, 10H), 2.18 (s, 3H), 2.35 (s, 2H), 3.17 (i.e. , J = 6.8 Hz, 2H), 4.80 (s, 2H), 5.11 (s, 2H), 5.44 (t, J = 6.8 Hz, 1H), 7.36 (m , 5H).

Step G: 1 - {[((5-Methyl-2-oxo-1,3-dioxol-4-en-4-yl) methoxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (117)

To a solution of the compound (123) (510 mg, 1.41 mmol) in ethanol (20 ml) was added 59 mg of Pd / C (5%), and the resulting mixture was stirred for 1 hour under a hydrogen atmosphere. Filtration and removal of the volatiles under reduced pressure afforded the crude product, which was purified by preparative LC / MS to afford 105 mg of the title compound. ¹ H-NMR (CD ₃ OD, 400 MHz): δ 1.52-1.36 (m, 10H), 2.16 (s, 3H), 2.27 (s, 2H), 3.22 (s , 2H), 4.86 (s, 2H).

(COMPARATIVE) EXAMPLE 36

Piperidinium 1 - {(1-methyl-3-oxobut-1-enyl) aminomethyl} -1-cyclohexane acetate (124)

2,4-pentanedione (103 μL, 1 mmol), gabapentin (171 mg, 1 mmol) and piperidine (99 μL, 1 mmol) were mixed in anhydrous methanol (10 mL). The resulting mixture was refluxed for 4 hours. Removal of the solvent under reduced pressure gave the title compound greater than 90% purity. ¹ H-NMR _(CDCl3, 400 MHz): δ 1.34 to 1.62 (m, 12H), 1.71 (m, 4H), 1.94 (s, 3H), 1.96 (s, 3H), 2.26 (s, 2H), 2.98 (m, 4H), 3.38 (d, J = 6Hz, 2H), 4.90 (s, 1H), 5.20 (s, br, 2H), 8.64 (t, J = 6 Hz, 1H). MS (ESI) m / z 252.35 (M-H).

(COMPARATIVE) EXAMPLE 37

Piperidinium 1- {1-1 (2-oxotetrahydrofuran-3-ylidene) ethylaminomethyl} -1-cyclohexane acetate (125)

2-Acetylbutyrolactone (108 μl, 1 mmol), gabapentin (171 mg, 1 mmol) and piperidine (99 μl, 1 mmol) were mixed in anhydrous methanol (10 ml). After refluxing for 6 hours, the solvent was removed under reduced pressure to afford the title compound greater than 90% purity. ¹ H-NMR _(CDCl3, 400 MHz): δ 1.34 to 1.62 (m, 12H), 1.71 (m, 4H), 1.94 (s, 3H), 2.24 (s, 2H), 2.81 (t, J = 7.6 Hz, 2H), 2.99 (m, 4H), 3.31 (d, J = 6.4 Hz, 2H), 4.23 (t, J = 7.6Hz, 2H), 5.17 (s, br, 2H), 8.64 (t, J = 6.4Hz, 1H). MS (ESI) m / z 280.34 (M-H ^- ).

(COMPARATIVE) EXAMPLE 38

Piperidinium 1 - {(2-carbomethoxycyclopent-1-enyl) aminomethyl} -1-cyclohexane acetate (126)

Methyl 2-oxocyclopentanecarboxylate (124 μL, 1 mmol), gabapentin (171 mg, 1 mmol) and piperidine (99 μL, 1 mmol) were mixed in anhydrous methanol (10 mL). After refluxing for 16 hours, the solvent was removed under reduced pressure to afford the title compound greater than 90% purity. ¹ H-NMR _(CDCl3, 400 MHz): δ 1.29 to 1.60 (m, 12H), 1.72 (m, 4H), 1.79 (m, J = 7.6 Hz, 2H) , 2.24 (s, 2H), 2.49 (t, J = 7.6Hz, 2H), 2.55 (t, J = 7.6Hz, 2H), 2.99 (m, 4H) , 3.24 (d, J = 6.8Hz, 2H), 3.63 (s, 3H), 5.06 (s, br, 2H), 7.93 (s, br, 1H). MS (ESI) m / z 294.36 (M-H).

(COMPARATIVE) EXAMPLE 39

Piperidinium 1 - {(1-methyl-2- (ethoxycarbonyl) -3-ethoxy-3-oxo-prop-1-enyl) -aminomethyl} -1-cyclohexane acetate (127)

Diethyl acetylmalonate (202mg, 1mmol), gabapentin (171mg, 1mmol) and piperidine (99μl, 1mmol) were mixed in anhydrous ethanol (10ml). After refluxing for 16 hours, the solvent was removed under reduced pressure to give the title compound of greater than 90% purity. ¹ H-NMR _(CDCl3, 400 MHz): δ 1.28 (t, J = 7.2 Hz, 6H), 1.38 to 1.64 (m, 12H), 1.75 (m, 4H) , 1.96 (s, 3H), 2.23 (s, 2H), 2.99 (m, 4H), 3.24 (d, J = 5.2Hz, 2H), 4.20 (q, J = 7.2 Hz, 4H), 4.35 (s, br, 2H), 7.79 (t, J = 5.2 Hz, 1H). MS (ESI) m / z 354.38 (M-H).

(COMPARATIVE) EXAMPLE 40

1 - {[(α- (2- (2-methyl-1,3-dioxolane-2-μL) carboxyisobutoxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (128)

Step A: 2-Methyl-1,3-dioxolane-2-carboxylic acid (129)

With stirring, to a mixture containing ethyl pyruvate (11.1 ml, 0.1 mol) and ethylene glycol (5.6 ml, 0.1 mol) in anhydrous dichloromethane (100 ml) at 0 ° C was boron trifluoride dietherate (6.4 ml, 0.05 mol) and a catalytic amount of acetic acid. The resulting mixture was stirred at 40 ° C for 16 h and then diluted with 100 mL of dichloromethane. The organic solution was washed successively with saturated sodium chloride solution (2 × 80 ml). The organic phase was separated and the combined organic extracts were concentrated. The residue was treated with 1N sodium hydroxide solution at room temperature. After stirring for 3 hours at room temperature (monitored by TLC), citric acid was added to adjust the pH to 4. The product was extracted with dichloromethane, dried over Na ₂ SO ₄ and concentrated to afford 5.1 g (38%) of the title compound (129) as a clear liquid. This material was used in the next reaction without further purification. ¹ H-NMR _(CDCl3, 400 MHz): δ 1.55 (s, 3H), 4.03 (m, 4H).

Step B: 1 - {[(α- (2- (2-Methyl-1,3-dioxolan-2-yl) carboxyisobutoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid benzyl ester (130)

A mixture containing 1 - {[(α-chloroisobutoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid benzyl ester (95) (1 g, 2.53 mmol), (129) (673 mg, 5.1 mmol), silver carbonate (557 mg, 2.53 mmol) and triethylamine (709 μl, 5.1 mmol) in chloroform was stirred at room temperature for 16 h. After filtration, the filtrate was concentrated. The resulting residue was purified by silica gel chromatography eluting with 15% ethyl acetate / hexane to afford 510 mg (41%) of the title compound (130). MS (ESI) m / z 492.40 (M + H ⁺ ).

Step C: 1 - {[(α- (2- (2-Methyl-1,3-dioxolan-2-yl) carboxyisobutoxy) carbonyl] aminomethyl} -1-cyclohexanoacetic acid (128)

A mixture of (130) (470 mg, 0.96 mmol) and 5% Pd-C (catalytic amount) in ethanol was stirred for 16 h under hydrogen at room temperature. Filtration and concentration gave 382 mg (100%) of the title compound (128). ¹ H-NMR _(CDCl3, 400 MHz): δ 0.96 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H), 1.32 to 1 , 58 (m, 10H), 1.59 (s, 3H), 2.06 (m, 1H), 2.32 (s, 2H), 3.26 (m, 2H), 4.08 (m, 4H), 5.29 (t, 1H, NH), 6.55 (d, J = 4.8Hz, 1H). MS (ESI) m / z 402.32 (M + H ⁺ ).

The acid form was quantitatively converted to its corresponding sodium salt by dissolving in water (5 ml), adding an equimolar amount of 0.5N NaHCO ₃ solution, followed by lyophilization.

EXAMPLE 41

In Vitro Determination of Caco-2 Cell Permeability of Prodrugs

The passive permeability of the prodrugs of the present invention can be evaluated in vitro using standard techniques well known in the art (See, e.g., Stewart et al., Pharm. Res., 1995, 12, 693). For example, passive permeability can be assessed by examining the flow of a prodrug across a cultured polarized cell monolayer (e.g., Caco-2 cells). Caco-2 cells obtained from a continuous culture (run less than 28) were placed in high density on Transwell polycarbonate filters. The cells were obtained with DMEM / 10% fetal calf serum + 0.1 mM non-essential amino acids + 2 mM L-Gln, 5% CO ₂ /95% O ₂ , 37 ° C until the experimental day. The permeability studies were performed apical at pH 6.5 (in 50 mM MES buffer containing 1 mM CaCl ₂ , 1 mM MgCl ₂ , 150 mM NaCl, 3 mM KCl, 1 mM NaH ₂ PO ₄ and 5 mM glucose) and pH 7.4 basolateral (in Hanks balanced saline containing 10 mM HEPES) in the presence of efflux pump inhibitors (250 μM MK-571, 250 μM verapamil, 1 mM ofloxacin). The inserts were placed in 12 or 24-well plates containing buffer and incubated at 37 ° C for 30 minutes. Prodrug (200 μM) was added to the apical or basolateral compartment (donor) and concentrations of the prodrug and / or released parent drug in the opposite compartment (recipient) were determined for 1 hour at intervals using LC / MS / MS. The values of apparent permeability (P _app ) were _calculated using the equation: P _app = V _r (dC / dt) / (AC ₀ ) calculated. Here, V _{r is} the volume of the recipient compartment in ml; dC / dt is the total flux of the prodrug and parent drug (μM / s), which is determined from the slope of the graphical representation of the concentration in the recipient compartment versus time; C ₀ is the initial concentration of the prodrug in μM; A is the area of the membrane in cm ² . Preferably, prodrugs having significant transcellular permeability exhibit a P _app of ≥ 1 x 10 ⁶ cm / s, and more preferably a P _app of ≥ 1 x 10 ^-5 cm / s, and even more preferably a P _app of ≥ 5 × 10 ^-5 cm / s. Typical P _app values obtained for prodrugs of GABA analogs are shown in the following table: connection P _app (apical-to-basolateral) (cm / s) P _app (basolateral-to-apical) (cm / s) Ratio AB / BA (51) 1.06 × 10 ^-4 1.25 × 10 ^-5 8.5 (56) 3.1 × 10 ^-5 2.0 × 10 ^-6 15.5 (62) 2.10 × 10 ^-5 6.40 × 10 ^-6 3.3 (68) 8.43 × 10 ^-5 2.26 × 10 ^-5 3.7 (69) 1.84 × 10 ^-4 5.22 × 10 ^-6 35.2 (70) 1.78 × 10 ^-5 1.68 × 10 ^-6 10.6 (71) 8.10 × 10 ^-5 1.99 × 10 ^-5 4.1 (72) 2.51 × 10 ^-5 1.26 × 10 ^-6 2.0 (77) 7.41 × 10 ^-5 1.43 × 10 ^-5 5.2 (78) 1.37 × 10 ^-4 2.46 × 10 ^-5 5.6 (80) 6.62 × 10 ^-5 8.75 × 10 ^-6 7.6 (81) 8.65 × 10 ^-5 1.27 × 10 ^-5 6.8 (82) 1.25 × 10 ^-4 1.82 × 10 ^-5 6.9 (83) 1.29 × 10 ^-5 4.48 × 10 ^-5 0.3 (84) 1.26 × 10 ^-4 1.57 × 10 ^-5 8.1 (89) 5.85 × 10 ^-5 2.34 × 10 ^-6 25.0 (90) 9.22 × 10 ^-5 5.75 × 10 ^-6 16.0

The data in this table shows that the prodrugs disclosed herein have high cellular permeability and should be well absorbed from the gut. With the exception of compound (83), the permeabilities apical-to-basolateral of these prodrugs exceed their permeabilities basolateral-to-apical. This suggests that these compounds may be substances for active transport mechanisms present in the apical membrane of Caco cells (although some components of this transcellular permeability may also be mediated by passive diffusion). The greater basolateral-to-apical permeability of (83) suggests that this compound may be subject to efflux across the basolateral membrane despite the presence of efflux pump inhibitors MK-571, verapamil and ofloxacin.

EXAMPLE 42

Intake of gabapentin following intracolonic administration of gabapentin or gabapentin prodrugs in rats

Continuous release oral dosage forms that release drug slowly over periods of 6-24 hours generally release a substantial portion of the dose within the colon. Thus, drugs suitable for use in such dosage forms preferably exhibit good colonic absorption. This experiment was conducted to evaluate the suitability of gabapentin prodrugs for use in a sustained release oral dosage form.

Step A: Administration Protocol

Rats were obtained commercially and were pre-cannulated in both the ascending colon and the jugular vein. The animals were conscious at the time of the experiment. All animals were starved overnight and up to 4 hours after dosing. Gabapentin or gabapentin prodrugs (59), (63), (69), (72), (77), (79), (85), (117) and (126) were used as a solution (in water or PEG 400). at a dose equivalent to 25 mg gabapentin per kg administered via the cannula directly into the colon. Blood samples (0.5 ml) were obtained at intervals from the jugular vein cannula for 8 hours and immediately quenched by the addition of acetonitrile / methanol to prevent further conversion of the prodrug. The blood samples were analyzed as described below.

Step B: Sample preparation for colon-absorbed drug

• 1. Empty 1.5 ml Eppendorf tubes were added to 300 μl of 50/50 acetonitrile / methanol and 20 μl of p-chlorophenylalanine as internal standard.
• 2. Rat blood was collected at various times and immediately 100 μl of blood was added to the Eppendorf tube and vortexed to mix.
• 3. 10 μl of gabapentin standard solution (0.04, 0.2, 1, 5, 25, 100 μg / ml) was added to 90 μl of blind rat blood to obtain a final calibration standard (0.004, 0.02, 0.1, 0 , 5, 2.5, 10 μg / ml). Then, to each tube was added 300 μl of 50/50 acetonitrile / methanol, followed by 20 μl of p-chlorophenylalanine.
• 4. The samples were vortexed and centrifuged at 14,000 rpm for 10 minutes.
• 5. The supernatant was taken for LC / MS / MS analysis.

Step C: LC / MS / MS analysis

An API 2000 LC / MS / MS spectrometer equipped with Shadmad 10ADVp binary pumps and a CTC HTS-PAL autosampler was used in the analysis. A Zorbax XDB C8 4.6 x 150 mm column was heated to 45 ° C during the analysis. The mobile phase was 0.1% formic acid (A) and acetonitrile with 0.1% formic acid (B). The gradient condition was: 1 min 5% B, then held in 3 min to 98% B, then 2.5 min at 98% B. The mobile phase was returned to 5% B for 2 min. A TurbolonSpray source was used at API 2000. The analysis was performed in positive ion mode and an MRM transition of 172/137 was used in the analysis of gabapentin (MRM transitions 426/198 for (59), 364/198 for (63), 392/198 for (69) , 316/198 for (72), 330/198 for (77), 330/198 for (79), 316/198 for (85) and 327,7 / 153,8 for (117) were used). 20 μl of the samples were injected. The peaks were integrated using Analyst 1.1 quantification software. Following a colonic administration of each of these prodrugs, the maximum plasma concentrations of gabapentin (C _max) and the area of considerable under the gabapentin plasma concentration-time curves (AUC) greater than (> 2 times) than that colonic of administration were produced by gabapentin itself. For example, prodrug (77) provided more than 10-fold higher gabapentin C _max as well as AUC values than gabapentin itself. These data demonstrate that compounds of the invention can be formulated as compositions that are useful for improved absorption and / or efficacy sustained release of GABA analogs to minimize the frequency of dosing due to the rapid systemic secretion of these GABA analogs.

EXAMPLE 43

Continued release of gabapentin following prodrug administration using osmotic minipump devices in beagle dogs

Gabapentin or the gabapentin prodrugs (77) and (82) (at a dose equivalent to 10 mg gabapentin per kg) were dissolved in a suitable solvent (e.g., water, PEG 400, etc.) and pre-weighed osmotic Alzet ^® Minipumpvomchtungen (Model 200ID) (Durect Corp., Cupertino, CA) filled. The filled alzets were pre-equilibrated by immersing in isotonic saline at 37 ° C for 3 hours and stored in sealed containers at 4 ° C overnight. The alzets were then administered orally to four fasting male beagle dogs (approximately 6.5 kg). The animals were fed for 4 hours after each dose. Blood samples (1.0 ml) were taken at intervals over 48 hours and immediately processed into plasma. The plasma samples were frozen and stored at -80 ° C until analyzed using the method described above. Both prodrugs delivered plasma gabapentin concentrations greater than 2 times the gabapentin concentration seen after administration of gabapentin even in the Alzet device 12 hours after dosing. These data further confirm that compounds of the invention can be formulated as compositions suitable for effective sustained release of GABA analogs.

(COMPARATIVE) EXAMPLE 44

Ingestion of pregabalin following intracolonic administration of pregabalin or pregabalin prodrugs in rats

The protocol of Example 41 was repeated with pregabalin and pregabalin prodrugs (110) and (112). Following a colonic administration of each of these prodrugs, the maximum plasma concentrations of pregabalin (C _max) and the area were under the pregabalin plasma concentration-time curves (AUC) significantly greater (> 2-times) than those obtained by colonic administration of Pregabalin itself were produced.

Claims (12)

A compound selected from 1 - {[(α-isobutanoyloxyethoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid and pharmaceutically acceptable salts, hydrates and solvates thereof. A compound according to claim 1 selected from 1 - {[(α-isobutanoyloxyethoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid and its sodium salt. A compound according to claim 1, which is 1 - {[(α-isobutanoyloxyethoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid. The compound of claim 1 which is the sodium salt of 1 - {[(α-isobutanoyloxyethoxy) carbonyl] aminomethyl} -1-cyclohexaneacetic acid. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier. A pharmaceutical composition for the treatment or prevention of epilepsy, depression, anxiety, psychosis, faintness, hypokinesia, headache, neurodegenerative disorders, panic, pain, inflammatory diseases, insomnia, gastrointestinal disorders or ethanol withdrawal syndrome in a subject comprising a therapeutically effective amount of a compound according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier. A pharmaceutical composition for the treatment or prevention of neuropathic pain, muscle or bone pain in a patient comprising a therapeutically effective amount of a compound of any of claims 1 to 4 and a pharmaceutically acceptable carrier. A compound according to any one of claims 1 to 4 for use in a method of treatment of a human or animal body by therapy. A compound according to any one of claims 1 to 4 for use in a method for the treatment or prevention of epilepsy, depression, anxiety, psychosis, faintness, hypokinesia, headache, neurodegenerative disorders, panic, pain, inflammatory diseases, insomnia, gastric ulcer disorders or ethanol withdrawal syndrome in a patient. A compound according to any one of claims 1 to 4 for use in a method of treating or preventing neuropathic pain, muscle or bone pain in a patient. Use of a compound according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment or prevention of epilepsy, depression, anxiety, psychosis, faintness, hypokinesia, headache, neurodegenerative disorders, panic, pain, inflammatory diseases, insomnia, gastrointestinal disorders or ethanol withdrawal syndrome in a patient. Use of a compound according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment or prevention of neuropathic pain, muscle or bone pain in a patient.